323 results on '"David J. Amor"'
Search Results
202. Registry- and Clinic-Based Analyses of Birth Defects and Syndromes Associated with Cleft Lip/Palate in Victoria, Australia
- Author
-
Nicky Kilpatrick, Jane Halliday, Merilyn Riley, Katrina Simms, Tiong Yang Tan, Susan M. White, and David J. Amor
- Subjects
Male ,Pediatrics ,medicine.medical_specialty ,Victoria ,Cleft Lip ,Population ,Dentistry ,Congenital Abnormalities ,Interviews as Topic ,Clinical study ,Risk Factors ,Humans ,Medicine ,Registries ,education ,education.field_of_study ,Chi-Square Distribution ,Cleft lip palate ,business.industry ,Infant, Newborn ,Syndrome ,Congenital cleft ,Cleft Palate ,Otorhinolaryngology ,Cohort ,Female ,Oral Surgery ,Congenital disease ,business - Abstract
Objective: To study the birth defects and syndromes associated with cleft lip and/or cleft palate in children born from 2000 through 2002 in Victoria, Australia, comparing data from the birth defects registry and detailed clinical assessment. Design, Setting, and Participants: Data recorded in the Victorian Birth Defects Register were retrieved for all children with cleft lip and/or palate born from 2000 through 2002. In parallel, a cohort of children with clefts was recruited from the two cleft centers in Victoria. Clinical data were collected using structured parental interview, clinical/dysmorphologic examination, and file review. Results: Victorian Birth Defects Register records of 312 children with cleft lip and/or palate were identified, and 53 children were recruited for the clinical study. The clinical study found a higher proportion of nonisolated clefts than were listed in the registry; this was largely due to the more detailed assessment, but some selection bias was possible. Poor growth and developmental delay were most likely to predict the presence of other birth defects or a syndrome diagnosis in a child with cleft lip and/or palate. The clinical study led to modifications to 16/53 (30.2%) of records in the Victorian Birth Defects Register. Conclusions: This study provides complementary registry- and clinic-based data on cleft lip and/or palate–associated malformations and syndrome diagnoses in Australian children and emphasizes the value of having a clinician experienced in dysmorphology involved in cleft services with ongoing reporting to the Victorian Birth Defects Register.
- Published
- 2009
203. Pallister-Killian syndrome caused by mosaicism for a supernumerary ring chromosome 12p
- Author
-
David J. Amor, David Francis, Alison Yeung, and Olivia Giouzeppos
- Subjects
Isochromosome ,Ring chromosome ,Aneuploidy ,Chromosome Disorders ,Biology ,Congenital Abnormalities ,Pallister–Killian syndrome ,polycyclic compounds ,Genetics ,medicine ,Humans ,Abnormalities, Multiple ,Ring Chromosomes ,Supernumerary ,In Situ Hybridization, Fluorescence ,Genetics (clinical) ,Chromosome 12 ,Chromosome Aberrations ,Chromosomes, Human, Pair 12 ,Mosaicism ,Karyotype ,Syndrome ,medicine.disease ,Chromosome Banding ,Child, Preschool ,Karyotyping ,Tetrasomy ,Female - Abstract
Pallister-Killian syndrome (PKS) is a rare but distinctive chromosomal syndrome distinguished by severe intellectual impairment, characteristic facial features, and variable structural anomalies. The characteristic cytogenetic abnormality in PKS is a supernumerary isochromosome 12p that confers mosaic tetrasomy. We describe a female child with PKS in whom tetrasomy 12p resulted from a supernumerary ring chromosome containing two copies of chromosome 12cen --> p13, a novel cytogenetic finding. The ring chromosome exhibited tissue-limited mosaicism, being absent in blood but detected in 38% of buccal mucosa cells and 41% of skin fibroblasts. Our patient demonstrated the typical dysmorphic characteristics of PKS, but her development was relatively advanced in comparison to children with isochromosome PKS. Her milder developmental phenotype may be attributable to differences in the mosaic distribution or the genomic content of the ring chromosome compared to mosaic isochromosome 12p.
- Published
- 2009
204. A review of known imprinting syndromes and their association with assisted reproduction technologies
- Author
-
Jane Halliday and David J. Amor
- Subjects
Beckwith-Wiedemann Syndrome ,Reproductive Techniques, Assisted ,Beckwith–Wiedemann syndrome ,Russell-Silver Syndrome ,Biology ,Epigenesis, Genetic ,Craniofacial Abnormalities ,Genomic Imprinting ,Diabetes mellitus genetics ,Pregnancy ,Angelman syndrome ,Happy puppet syndrome ,Diabetes Mellitus ,medicine ,Humans ,Imprinting (psychology) ,Chromosomes, Human, Pair 14 ,Genetics ,Rehabilitation ,Obstetrics and Gynecology ,Syndrome ,DNA Methylation ,Uniparental Disomy ,medicine.disease ,Uniparental disomy ,Reproductive Medicine ,Pseudohypoparathyroidism ,Female ,Angelman Syndrome ,Genomic imprinting ,Prader-Willi Syndrome - Abstract
An association between assisted reproduction technologies (ART) and abnormal genomic imprinting in humans has been recognized for several years; however, the magnitude of this risk and the spectrum of imprinting syndromes to which the risk applies remains unknown. Nine human imprinting syndromes have been identified but current evidence links ART with only three: Beckwith-Wiedemann syndrome, Angelman syndrome and the newly described maternal hypomethylation syndrome. There is currently a lack of evidence linking ART with the remaining six imprinting syndromes: Prader-Willi syndrome, Russell-Silver syndrome, maternal and paternal uniparental disomy of chromosome 14, pseudohypoparathyroidism type 1b and transient neonatal diabetes. Evidence from clinical reports suggests that the association between imprinting syndromes and ART may be restricted to syndromes where the imprinting change takes the form of hypomethylation on the maternal allele. In contrast, studies of gametes and early embryos suggest that ART can be associated with hypermethylation as well as hypomethylation, with imprinting changes occurring on paternal as well as maternal alleles. The health effects of ART-associated imprinting changes may also extend beyond the nine recognized imprinting syndromes.
- Published
- 2008
205. Spondylocostal dysostosis in a pregnancy complicated by confined placental mosaicism for tetrasomy 9p
- Author
-
Sonya Bacic, Amber Boys, David J. Amor, David Coman, Duncan B. Sparrow, Sally L. Dunwoodie, and Ravi Savarirayan
- Subjects
Male ,Pathology ,medicine.medical_specialty ,Hydrops Fetalis ,Placenta ,Chorionic villus sampling ,Ribs ,Prenatal diagnosis ,Biology ,LFNG ,Pregnancy ,Hydrops fetalis ,Genetics ,medicine ,Humans ,Abnormalities, Multiple ,Confined placental mosaicism ,Genetics (clinical) ,medicine.diagnostic_test ,Mosaicism ,Infant, Newborn ,Dysostoses ,Anatomy ,Aneuploidy ,medicine.disease ,Spine ,Spondylocostal dysostosis ,Chorionic Villi Sampling ,Child, Preschool ,Karyotyping ,Tetrasomy ,Amniocentesis ,Female ,Tetrasomy 9p ,Chromosomes, Human, Pair 9 ,Nuchal Translucency Measurement - Abstract
The spondylocostal dysostoses (SCD) are a clinically and genetically heterogeneous group of disorders characterized by defects of vertebral segmentation and rib abnormalities. We report on the diagnosis of two siblings with SCD. Diagnosis was first made in a female infant following a pregnancy that was complicated by early fetal hydrops and a nuchal translucency of 8.2 mm in the first trimester. The clinical picture was complicated by the co-existent diagnosis of confined placental mosaicism (CPM) for tetrasomy 9p. To our knowledge, this is the first report of CPM for tetrasomy 9p. Postnatally the diagnosis of SCD was made on the basis of radiographic findings comprising multiple anomalies of the cervical and thoracic vertebrae and multiple fused and dysplastic ribs. Radiographic investigation of other family members showed that the infant's 4-year-old sibling had fusion of four ribs on the right side, indicating a less severe form of SCD. Testing of the genes DLL3, MESP2, and LFNG did not identify a mutation, suggesting that the siblings may have a new molecular subtype of SCD.
- Published
- 2008
206. PGD gender selection for non-Mendelian disorders with unequal sex incidence
- Author
-
Carolyn Cameron and David J. Amor
- Subjects
Male ,Non-Mendelian inheritance ,Offspring ,Preimplantation genetic diagnosis ,symbols.namesake ,Sex Factors ,Risk Factors ,Prenatal Diagnosis ,Humans ,Medicine ,Genetic Predisposition to Disease ,Sex Preselection ,Autistic Disorder ,Sex Distribution ,Preimplantation Diagnosis ,Selection (genetic algorithm) ,Genetics ,business.industry ,Incidence (epidemiology) ,Rehabilitation ,Obstetrics and Gynecology ,Genetic Diseases, X-Linked ,Genetic Diseases, Y-Linked ,medicine.disease ,Developmental disorder ,Reproductive Medicine ,Mendelian inheritance ,symbols ,Autism ,Female ,business ,Demography - Abstract
Preimplantation genetic diagnosis (PGD) was originally developed for couples whose potential offspring were at risk of severe Mendelian disorders, but has since been extended to other indications. One possible use of PGD is to perform gender selection for couples whose offspring are at increased risk of disorders that do not follow Mendelian inheritance, but which are substantially more common in one sex than another (unequal sex incidence). Here, we examine the clinical and ethical issues to be considered prior to offering PGD gender selection to reduce the risk of a child being affected by a non-Mendelian condition with unequal sex incidence. Factors to be considered include: the risk that a child of either sex will be affected by the condition; the overall reduction in risk provided by gender selection and the potential harms of the procedure. Consideration should also be given to the interests of the family and the child to be born, the seriousness of the condition and the couple's procreative autonomy. To illustrate these issues we use the example of autism, a non-Mendelian disorder that is considerably more common in males than in females.
- Published
- 2008
207. Identification of 34 Novel and 56 Known FOXL2 Mutations in Patients With Blepharophimosis Syndrome
- Author
-
Anne De Paepe, Patricia Delbeke, Nina Øyen, Françoise Meire, Astrid S. Plomp, Louise C. Wilson, Gabriele Gillessen-Kaesbach, Bart P. Leroy, David Mowat, Jill Clayton-Smith, Yvonne M.C. Hendriks, Nicole Van Regemorter, Philippe Touraine, Virginia Kimonis, Christian Decock, Diane Beysen, Luitgard M. Neumann, Paul Laissue, Dagmar Wieczorek, Kathleen A. Leppig, Arthur Grix, Sarah De Jaegere, Philippe Bouchard, Marc Fellous, Regina Ensenauer, Thomy de Ravel, Sophie Christin-Maitre, David T. Miller, Elfride De Baere, Rachel Laframboise, David J. Amor, Friedrich Ebinger, Raoul C.M. Hennekam, Reiner A. Veitia, Dalit Barel, Clinical sciences, Medical Genetics, Netherlands Institute for Neuroscience (NIN), Amsterdam Neuroscience, Amsterdam Public Health, Paediatric Genetics, and Human Genetics
- Subjects
Adult ,Forkhead Box Protein L2 ,Male ,Adolescent ,Child, preschool ,Genotype ,Nonsense mutation ,DNA Mutational Analysis ,Molecular Sequence Data ,Mutation, Missense ,Locus (genetics) ,Biology ,Blepharophimosis ,Primary Ovarian Insufficiency ,Frameshift mutation ,Genetics ,medicine ,Missense mutation ,Humans ,Amino Acid Sequence ,Forkhead Transcription Factors/genetics ,Child ,Frameshift Mutation ,Eyelids/abnormalities ,Genetics (clinical) ,Infant, Newborn ,Eyelids ,Infant ,Forkhead Transcription Factors ,Primary Ovarian Insufficiency/genetics ,Middle Aged ,medicine.disease ,Pedigree ,Forkhead box L2 ,Phenotype ,Codon, Nonsense ,young adult ,Female ,Sequence Alignment ,Blepharophimosis/genetics - Abstract
Blepharophimosis syndrome (BPES) is caused by loss-of-function mutations in the single-exon forkhead transcription factor gene FOXL2 and by genomic rearrangements of the FOXL2 locus. Here, we focus on 92 new intragenic FOXL2 mutations, 34 of which are novel. Specifically, we found 10 nonsense mutations (11%), 13 missense mutations (14%), 40 deletions or insertions leading to a frameshift (43%), and 29 in-frame changes (32%), of which 28 (30%) lead to a polyalanine expansion. This study confirms the existence of two previously described mutational hotspots. Moreover, we gained novel insights in genotype-phenotype correlations, emphasizing the need to interpret genotype-phenotype correlations individually and always in the context of further clinical observations. (C) 2008 Wiley-Liss, Inc
- Published
- 2008
208. Mutations in smooth muscle α-actin (ACTA2) lead to thoracic aortic aneurysms and dissections
- Author
-
Chul Ahn, Chander Raman, Steve Scherer, Christina L. Papke, Anthony L. Estrera, Van Tran-Fadulu, Richard A. Lewis, Robert Yu, Hariyadarshi Pannu, Colin E. Willoughby, Vivienne McConnell, Marcia C. Willing, Dong H. Kim, Sanjay Shete, Elizabeth Sparks, Nili Avidan, David J. Amor, Poyee P. Tung, Dianna M. Milewicz, Hazim J. Safi, Scott Bourgeois, Dongchuan Guo, L. Maximilian Buja, Lesley C. Adès, and Dianne N. Abuelo
- Subjects
Male ,Aortic Aneurysm, Thoracic ,biology ,Myocytes, Smooth Muscle ,Mutation, Missense ,MYLK ,macromolecular substances ,Anatomy ,medicine.disease ,Actins ,Pedigree ,Familial thoracic aortic aneurysm ,Aortic Dissection ,Smooth muscle ,cardiovascular system ,Genetics ,biology.protein ,MYH11 ,medicine ,Humans ,Female ,Genetic Predisposition to Disease ,cardiovascular diseases ,ACTA2 ,Aorta - Abstract
The major function of vascular smooth muscle cells (SMCs) is contraction to regulate blood pressure and flow. SMC contractile force requires cyclic interactions between SMC alpha-actin (encoded by ACTA2) and the beta-myosin heavy chain (encoded by MYH11). Here we show that missense mutations in ACTA2 are responsible for 14% of inherited ascending thoracic aortic aneurysms and dissections (TAAD). Structural analyses and immunofluorescence of actin filaments in SMCs derived from individuals heterozygous for ACTA2 mutations illustrate that these mutations interfere with actin filament assembly and are predicted to decrease SMC contraction. Aortic tissues from affected individuals showed aortic medial degeneration, focal areas of medial SMC hyperplasia and disarray, and stenotic arteries in the vasa vasorum due to medial SMC proliferation. These data, along with the previously reported MYH11 mutations causing familial TAAD, indicate the importance of SMC contraction in maintaining the structural integrity of the ascending aorta.
- Published
- 2007
209. Two siblings with 46,XY DSD, congenital adrenal hypoplasia, aniridia, craniofacial, and skeletal abnormalities and intrauterine growth retardation: A new syndrome?
- Author
-
David J. Amor, David Coman, and Susan M. White
- Subjects
Male ,Pediatrics ,medicine.medical_specialty ,Bone and Bones ,Genetics ,medicine ,Humans ,Abnormalities, Multiple ,IMAGe Syndrome ,Sibling ,Craniofacial ,Aniridia ,Genetics (clinical) ,Fetal Growth Retardation ,Growth retardation ,business.industry ,Skull ,Infant, Newborn ,Syndrome ,Anatomy ,medicine.disease ,Hypoplasia ,Face ,Karyotyping ,Congenital adrenal hypoplasia ,Skeletal abnormalities ,business ,Adrenal Insufficiency - Abstract
We report on two siblings with an unusual constellation of congenital anomalies comprising 46,XY disorder of sex development (DSD), congenital adrenal hypoplasia, aniridia, dysmorphic facial features, intrauterine growth retardation, and minor skeletal abnormalities. This combination of abnormalities is yet to be recognized in the medical literature. As such, we propose that our patients represent either a new dysmorphic syndrome or a thus far unrecognized variation of a known syndrome, such as IMAGe syndrome. The sibling recurrence suggests autosomal recessive or X-linked patterns of inheritance.
- Published
- 2007
210. Keipert syndrome (Nasodigitoacoustic syndrome) is X-linked and maps to Xq22.2–Xq28
- Author
-
Agnes Bankier, Melanie Bahlo, David J. Amor, and Hans-Henrik M. Dahl
- Subjects
Adult ,Male ,Genetic Linkage ,FG syndrome ,Hearing loss ,Deafness ,Nose ,Fingers ,Gene mapping ,Genetic linkage ,Nasodigitoacoustic syndrome ,Genetics ,medicine ,Humans ,Abnormalities, Multiple ,Genetics (clinical) ,X chromosome ,Dystonia ,Chromosomes, Human, X ,business.industry ,Chromosome Mapping ,Infant ,Genetic Diseases, X-Linked ,Syndrome ,Toes ,medicine.disease ,Pedigree ,Xq28 ,Female ,medicine.symptom ,business - Abstract
Keipert syndrome is a rare condition comprising sensorineural deafness associated with facial and digital abnormalities. To date, Keipert syndrome has been reported in six male patients including two sib pairs; however the genetic basis of Keipert syndrome is yet to be elucidated. We report on the diagnosis of Keipert syndrome in the nephew of the brothers in the first report of Keipert syndrome, with a pedigree consistent with X-linked recessive inheritance. Linkage analysis using microsatellite markers along the X-chromosome suggests that the gene for Keipert syndrome is located in the region Xq22.2-Xq28. We postulate the Keipert syndrome is caused by a novel gene at Xq22.2-Xq28.
- Published
- 2007
211. Complete callosal agenesis, pontocerebellar hypoplasia, and axonal neuropathy due to AMPD2 loss
- Author
-
Vesna Lukic, Elliott H. Sherr, Martin B. Delatycki, Catherine J. Bromhead, George McGillivray, Joe C H Sim, Eppie M. Yiu, Kate Pope, Melanie Bahlo, Richard J. Leventer, Ashley P L Marsh, Monique M. Ryan, Paul J. Lockhart, Rick M. Tankard, and David J. Amor
- Subjects
Pathology ,medicine.medical_specialty ,Pontocerebellar hypoplasia ,Postnatal microcephaly ,Biology ,Corpus callosum ,medicine.disease_cause ,Article ,03 medical and health sciences ,0302 clinical medicine ,Genetic linkage ,medicine ,Agenesis of the corpus callosum ,Exome ,Genetics (clinical) ,Genetics ,0303 health sciences ,Mutation ,030305 genetics & heredity ,medicine.disease ,Peripheral neuropathy ,Neurology (clinical) ,030217 neurology & neurosurgery - Abstract
Objective: To determine the molecular basis of a severe neurologic disorder in a large consanguineous family with complete agenesis of the corpus callosum (ACC), pontocerebellar hypoplasia (PCH), and peripheral axonal neuropathy. Methods: Assessment included clinical evaluation, neuroimaging, and nerve conduction studies (NCSs). Linkage analysis used genotypes from 7 family members, and the exome of 3 affected siblings was sequenced. Molecular analyses used Sanger sequencing to perform segregation studies and cohort analysis and Western blot of patient-derived cells. Results: Affected family members presented with postnatal microcephaly and profound developmental delay, with early death in 3. Neuroimaging, including a fetal MRI at 30 weeks, showed complete ACC and PCH. Clinical evaluation showed areflexia, and NCSs revealed a severe axonal neuropathy in the 2 individuals available for electrophysiologic study. A novel homozygous stopgain mutation in adenosine monophosphate deaminase 2 ( AMPD2 ) was identified within the linkage region on chromosome 1. Molecular analyses confirmed that the mutation segregated with disease and resulted in the loss of AMPD2. Subsequent screening of a cohort of 42 unrelated individuals with related imaging phenotypes did not reveal additional AMPD2 mutations. Conclusions: We describe a family with a novel stopgain mutation in AMPD2 . We expand the phenotype recently described as PCH type 9 to include progressive postnatal microcephaly, complete ACC, and peripheral axonal neuropathy. Screening of additional individuals with related imaging phenotypes failed to identify mutations in AMPD2 , suggesting that AMPD2 mutations are not a common cause of combined callosal and pontocerebellar defects.
- Published
- 2015
212. Detection of skewed X-chromosome inactivation in Fragile X syndrome and X chromosome aneuploidy using quantitative melt analysis
- Author
-
Sylvia A Metcalfe, Quang M. Bui, Cindy Skinner, Charles E. Schwartz, David J. Amor, Elva Z. Shi, David E. Godler, Yoshimi Inaba, Amy S Herlihy, Xin Li, John L. Hopper, Howard R. Slater, David Francis, and Randi J Hagerman
- Subjects
Male ,Aneuploidy ,Gene Expression ,Review Article ,Nucleic Acid Denaturation ,Fragile X Mental Retardation Protein ,0302 clinical medicine ,X Chromosome Inactivation ,80 and over ,Child ,X chromosome ,Aged, 80 and over ,Genetics ,0303 health sciences ,Exons ,Middle Aged ,Fragile X syndrome ,Child, Preschool ,030220 oncology & carcinogenesis ,Molecular Medicine ,Female ,Human ,Adult ,Adolescent ,Intellectual and Developmental Disabilities (IDD) ,Immunology ,and over ,Biology ,Y chromosome ,X-inactivation ,Chromosomes ,03 medical and health sciences ,Rare Diseases ,medicine ,Humans ,Saliva ,Preschool ,Molecular Biology ,Skewed X-inactivation ,030304 developmental biology ,Aged ,Chromosomes, Human, X ,Infant, Newborn ,Chromosome ,Infant ,DNA ,DNA Methylation ,medicine.disease ,Newborn ,FMR1 ,Molecular biology ,Introns ,Brain Disorders ,Fragile X Syndrome ,CpG Islands ,Biochemistry and Cell Biology - Abstract
Methylation of the fragile X mental retardation 1 (FMR1) exon 1/intron 1 boundary positioned fragile X related epigenetic element 2 (FREE2), reveals skewed X-chromosome inactivation (XCI) in fragile X syndrome full mutation (FM: CGG > 200) females. XCI skewing has been also linked to abnormal X-linked gene expression with the broader clinical impact for sex chromosome aneuploidies (SCAs). In this study, 10 FREE2 CpG sites were targeted using methylation specific quantitative melt analysis (MS-QMA), including 3 sites that could not be analysed with previously used EpiTYPER system. The method was applied for detection of skewed XCI in FM females and in different types of SCA. We tested venous blood and saliva DNA collected from 107 controls (CGG P P
- Published
- 2015
213. Identification of Males with Cryptic Fragile X Alleles by Methylation-Specific Quantitative Melt Analysis
- Author
-
Paulina Morales, Howard R. Slater, Angelica M. Alliende, David J. Amor, Cesar Trigo, Lorena Santa María, Isabel Salas, Desirée du Sart, David Francis, Xin Li, Bianca Curotto, Solange M. Aliaga, David E. Godler, and Víctor Faundes
- Subjects
0301 basic medicine ,Proband ,Adult ,Male ,Adolescent ,Clinical Biochemistry ,Biology ,Polymerase Chain Reaction ,law.invention ,Cohort Studies ,03 medical and health sciences ,Fragile X Mental Retardation Protein ,Young Adult ,law ,medicine ,Humans ,Allele ,Child ,Polymerase chain reaction ,Alleles ,Southern blot ,Genetics ,Mosaicism ,Biochemistry (medical) ,Infant ,DNA Methylation ,Middle Aged ,medicine.disease ,FMR1 ,Fragile X syndrome ,Blot ,Blotting, Southern ,030104 developmental biology ,Genetic Techniques ,Child, Preschool ,Fragile X Syndrome ,Autism ,CpG Islands - Abstract
BACKGROUND FMR1 full mutations (FMs) (CGG expansion >200) in males mosaic for a normal ( METHODS We used methylation-specific quantitative melt analysis (MS-QMA) to determine the prevalence of cryptic FM alleles in 2 independent cohorts of male patients (994 from Chile and 2392 from Australia) referred for FXS testing from 2006 to 2013. All MS-QMA–positive cases were retested with commercial triplet primed PCR, methylation-sensitive Southern blot, and a methylation-specific EpiTYPER-based test. RESULTS All 38 FMs detected with the standard 2-step protocol were detected with MS-QMA. However, MS-QMA identified methylation mosaicism in an additional 15% and 11% of patients in the Chilean and Australian cohorts, respectively, suggesting the presence of a cryptic FM. Of these additional patients, 57% were confirmed to carry cryptic expanded alleles in blood, buccal mucosa, or saliva samples. Further confirmation was provided by identifying premutation (CGG 55–199) alleles in mothers of probands with methylation-sensitive Southern blot. Neurocognitive assessments showed that low-level mosaicism for cryptic FM alleles was associated with cognitive impairment or autism. CONCLUSIONS A substantial number of mosaic FM males who have cognitive impairment or autism are not diagnosed with the currently recommended 2-step testing protocol and can be identified with MS-QMA as a first-line test.
- Published
- 2015
214. Familial cortical dysplasia caused by mutation in the mammalian target of rapamycin regulator NPRL3
- Author
-
Joe C, Sim, Thomas, Scerri, Miriam, Fanjul-Fernández, Jessica R, Riseley, Greta, Gillies, Kate, Pope, Hanna, van Roozendaal, Julian I, Heng, Simone A, Mandelstam, George, McGillivray, Duncan, MacGregor, Lakshminarayanan, Kannan, Wirginia, Maixner, A Simon, Harvey, David J, Amor, Martin B, Delatycki, Peter B, Crino, Melanie, Bahlo, Paul J, Lockhart, and Richard J, Leventer
- Subjects
Male ,Epilepsy ,Child, Preschool ,Malformations of Cortical Development, Group I ,TOR Serine-Threonine Kinases ,GTPase-Activating Proteins ,Mutation ,Humans ,Female ,Epilepsies, Partial ,Child ,Pedigree ,Signal Transduction - Abstract
We describe first cousin sibling pairs with focal epilepsy, one of each pair having focal cortical dysplasia (FCD) IIa. Linkage analysis and whole-exome sequencing identified a heterozygous germline frameshift mutation in the gene encoding nitrogen permease regulator-like 3 (NPRL3). NPRL3 is a component of GAP Activity Towards Rags 1, a negative regulator of the mammalian target of rapamycin complex 1 signaling pathway. Immunostaining of resected brain tissue demonstrated mammalian target of rapamycin activation. Screening of 52 unrelated individuals with FCD identified 2 additional patients with FCDIIa and germline NPRL3 mutations. Similar to DEPDC5, NPRL3 mutations may be considered as causal variants in patients with FCD or magnetic resonance imaging-negative focal epilepsy.
- Published
- 2015
215. Hemispheric cortical dysplasia secondary to a mosaic somatic mutation in MTOR
- Author
-
Martin B. Delatycki, Simon Harvey, Thomas S. Scerri, Greta Gillies, Kate Pope, Richard J. Leventer, Ashley P L Marsh, William Maixner, Paul J. Lockhart, David J. Amor, Melanie Bahlo, Duncan MacGregor, and Peter B. Crino
- Subjects
Male ,Pathology ,medicine.medical_specialty ,Mutation, Missense ,Biology ,medicine.disease_cause ,Article ,Germline mutation ,medicine ,Missense mutation ,Humans ,PI3K/AKT/mTOR pathway ,Neurons ,Mutation ,Epilepsy ,TOR Serine-Threonine Kinases ,Brain ,Infant ,Cortical dysplasia ,medicine.disease ,Magnetic Resonance Imaging ,Malformations of Cortical Development ,Dysplasia ,Positron-Emission Tomography ,Immunohistochemistry ,Histopathology ,Neurology (clinical) - Abstract
Objective: To define causative somatic mutations in resected brain tissue from an infant with intractable epilepsy secondary to hemispheric cortical dysplasia. Methods: Whole-exome sequencing was conducted on genomic DNA derived from both resected brain tissue and peripheral blood leukocytes. Comparison of the brain vs blood sequencing results was performed using bioinformatic methods designed to detect low-frequency genetic variation between tissue pairs. Results: Histopathology of the resected tissue showed dyslamination and dysmorphic neurons, but no balloon cells, consistent with focal cortical dysplasia type IIa. mTOR activation was observed by immunohistochemistry in the dysplasia. A missense mutation (c.4487T>G; p.W1456G) was detected in the FAT domain of MTOR in DNA from the dysplasia but not in lymphocytes. The mutation is predicted damaging (i.e., leading to mTOR activation) and was observed as a low-level mosaic with 8% of cells being heterozygous for the variant. Conclusions: We report the novel finding of an MTOR mutation associated with nonsyndromic cortical dysplasia. Somatic-specific mutations in MTOR and related genes should be considered in a broader spectrum of patients with hemispheric malformations and more restricted forms of cortical dysplasia.
- Published
- 2015
216. Familial cortical dysplasia type IIA caused by a germline mutation in DEPDC5
- Author
-
Rosemary Burgess, Greta Gillies, Simone Mandelstam, William Maixner, Leanne M. Dibbens, Chung Wo Chow, Samuel F. Berkovic, Richard J. Leventer, Thomas S. Scerri, David J. Amor, Martin B. Delatycki, Jessica R. Riseley, Paul J. Lockhart, Graeme D. Jackson, AS Harvey, Ingrid E. Scheffer, Melanie Bahlo, Peter B. Crino, Kate Pope, Scerri, Thomas, Riseley, Jessica R, Gillies, Greta, Pope, Kate, Burgess, Rosemary, Mandelstam, Simone A, Dibbens, Leanne Michelle, Chow, Chung W, Maixner, Wirginia, Harvey, Anthony Simon, Jackson, Graeme D, Amor, David J, Delatycki, Martin, Crino, Peter B, Berkovic, Samuel F, Scheffer, Ingrid E, Bahlo, Melanie, Lockhart, Paul, and Leventer, Richard
- Subjects
focal epilepsy ,Pathology ,medicine.medical_specialty ,Clinical Neurology ,medicine.disease_cause ,AKT3 ,Epilepsy ,Germline mutation ,rapamycin activation ,medicine ,Mutation ,business.industry ,General Neuroscience ,Neurosciences ,Cortical dysplasia ,NPRL3 ,medicine.disease ,DEPDC5 ,DEPDC5 mutation ,cortical malformations ,mTOR ,Neurology (clinical) ,business ,Brief Communications ,focal cortical dysplasia ,Immunostaining - Abstract
Whole-exome sequencing of two brothers with drug-resistant, early-onset, focal epilepsy secondary to extensive type IIA focal cortical dysplasia identified a paternally inherited, nonsense variant of DEPDC5 (c.C1663T, p.Arg555*). This variant has previously been reported to cause familial focal epilepsy with variable foci in patients with normal brain imaging. Immunostaining of resected brain tissue from both brothers demonstrated mammalian target of rapamycin (mTOR) activation. This report shows the histopathological features of cortical dysplasia associated with a DEPDC5 mutation, confirms mTOR dysregulation in the malformed tissue and expands the spectrum of neurological manifestations of DEPDC5 mutations to include severe phenotypes with large areas of cortical malformation. Refereed/Peer-reviewed
- Published
- 2015
217. Health and developmental outcome of children following prenatal diagnosis of confined placental mosaicism
- Author
-
Mark D. Pertile, Jane Halliday, David J. Amor, Wee Thong Neo, Elizabeth Waters, and Helen Heussler
- Subjects
Male ,medicine.medical_specialty ,Developmental Disabilities ,Health Status ,Placenta ,Chorionic villus sampling ,Prenatal diagnosis ,Congenital Abnormalities ,Cohort Studies ,Pregnancy ,Risk Factors ,Prenatal Diagnosis ,parasitic diseases ,Humans ,Medicine ,Child ,Confined placental mosaicism ,Genetics (clinical) ,Retrospective Studies ,Fetal Growth Retardation ,medicine.diagnostic_test ,Mosaicism ,business.industry ,Obstetrics ,Incidence ,Incidence (epidemiology) ,Pregnancy Outcome ,Obstetrics and Gynecology ,Retrospective cohort study ,medicine.disease ,Child, Preschool ,embryonic structures ,Cohort ,Female ,business ,human activities ,Cohort study - Abstract
Objective To determine the long-term health and development of a cohort of children in whom confined placental mosaicism (CPM) was diagnosed at prenatal diagnosis. Methods A retrospective cohort study was performed comparing 36 children in whom CPM had been diagnosed prenatally with 195 controls subjects in whom a normal karyotype had been detected prenatally. Data comprising birth information, health, health service utilisation, growth, development, behaviour, and the family were collected by a maternal questionnaire administered when the subjects were aged between 4 and 11 years. Results CPM cases did not differ from controls across a broad range of health measures and there were no major health problems or birth defects among the CPM group. No increase was detected in the incidence of intrauterine growth retardation (IUGR) among CPM cases; however, postnatal growth was reduced compared with controls (p = 0.047). Development and behaviour in CPM cases was similar to that of controls. Conclusions The prenatal diagnosis of CPM is not associated with an increased risk of birth defects or developmental problems, but may be associated with decreased growth. Copyright (C) 2006 John Wiley & Sons, Ltd.
- Published
- 2006
218. YPEL1 overexpression in early avian craniofacial mesenchyme causes mandibular dysmorphogenesis by up-regulating apoptosis
- Author
-
Kerry A. Miller, Tiong Yang Tan, Christopher T. Gordon, Peter G. Farlie, and David J. Amor
- Subjects
Genetics ,Transcriptional Activation ,biology ,Craniofacial abnormality ,Mesenchyme ,Neural crest ,Bone morphogenetic protein ,medicine.disease ,Facial Bones ,Cell biology ,Avian Proteins ,medicine.anatomical_structure ,DiGeorge syndrome ,Gene duplication ,biology.protein ,medicine ,Morphogenesis ,Animals ,Sonic hedgehog ,Craniofacial ,Chickens ,Developmental Biology - Abstract
Background: The YPEL (Yippee-like) gene family comprises five highly conserved members (YPEL1-5), but their biological function remains largely unknown. Early studies of YPEL1 function suggested that it plays a role in the development of structures derived from the pharyngeal arches. Human YPEL1 localises to distal chromosome 22q11.2 and copy number changes at this locus lead to diverse phenotypes that include facial dysmorphism, facial asymmetry, and palatal anomalies comprising the distal 22q11.2 deletion/duplication syndromes (OMIM 611867). We therefore investigated the role of chick YPEL1 in craniofacial development using ex vivo and in vivo approaches in the avian model. Results: We found that retroviral-mediated in vivo overexpression of YPEL1 causes abnormal mandibular morphogenesis associated with increased apoptosis and involvement of the BMP/MSX pathway. Conclusions: Our results suggest that YPEL1 expression is regulated by bone morphogenetic protein signaling and suggest a role for YPEL1 in the pathogenesis of the craniofacial abnormalities observed in humans with distal chromosome 22q11.2 deletions or duplications. Developmental Dynamics 244:1022–1030, 2015. © 2015 Wiley Periodicals, Inc.
- Published
- 2014
219. Mosaic monosomy of a neocentric ring chromosome maps brachyphalangy and growth hormone deficiency to 13q31.1-13q32.3
- Author
-
Ravi Savarirayan, David J. Amor, Lucille Voullaire, K. H. Andy Choo, and Karen Bentley
- Subjects
Male ,Monosomy ,Neocentromere ,Marker chromosome ,Ring chromosome ,Locus (genetics) ,Biology ,Fingers ,Genetics ,medicine ,Humans ,Abnormalities, Multiple ,Ring Chromosomes ,Child ,Growth Disorders ,In Situ Hybridization, Fluorescence ,Genetics (clinical) ,Chromosome 13 ,Chromosome Aberrations ,Chromosomes, Human, Pair 13 ,13q deletion syndrome ,Human Growth Hormone ,Mosaicism ,Chromosome Mapping ,Karyotype ,medicine.disease ,Chromosome Banding ,Karyotyping ,Chromosome Deletion ,Hand Deformities, Congenital - Abstract
We describe a boy with moderate intellectual disability associated with distinctive hand malformations (hypoplastic and angel-shaped middle phalanges) and partial growth hormone (GH) deficiency associated with mosaic deletion of 13q31.1-13q32.3. The deleted segment was mapped to a 20-Mb region bounded by BACs RP11-1143C2 and RP11-139C1, narrowing the previously described locus for hand malformations at this region and suggesting that a locus for GH deficiency is also present at this location. The deleted segment contains at least three candidate genes, glypican-5, FARP1 and SOX21, that may be contributing to the phenotype in this boy. In a significant proportion (approximately 50%) of cells, the deleted region is present as a supernumerary ring chromosome stabilized by the formation of a neocentromere at 13q31-q32, within a region with a known propensity for neocentromere formation. The ring chromosome appears to be prone to low-level misdivision and loss in vitro which, in vivo, must be countered by selection for the balanced karyotype because the level of mosaicism has remained stable over 13 years.
- Published
- 2005
220. Building the centromere: from foundation proteins to 3D organization
- Author
-
Huseyin Sumer, Paul Kalitsis, David J. Amor, and K. H. Andy Choo
- Subjects
Genetics ,Heterochromatin ,Kinetochore ,Centromere ,Proteins ,Locus (genetics) ,macromolecular substances ,Cell Biology ,Biology ,Models, Biological ,Zea mays ,Core domain ,Chromatin ,Cell biology ,chemistry.chemical_compound ,chemistry ,Yeasts ,Animals ,Humans ,Kinetochores ,Mitosis ,DNA - Abstract
At each mitosis, accurate segregation of every chromosome is ensured by the assembly of a kinetochore at each centromeric locus. Six foundation kinetochore proteins that assemble hierarchically and co-dependently have been identified in vertebrates. CENP-A, Mis12, CENP-C, CENP-H and CENP-I localize to a core domain of centromeric chromatin. The sixth protein, CENP-B, although not essential in higher eukaryotes, has homologues in fission yeast that bind pericentric DNA and are essential for heterochromatin formation. Foundation kinetochore proteins have various roles and mutual interactions, and their associations with centromeric DNA and heterochromatin create structural domains that support the different functions of the centromere. Advances in molecular and microscopic techniques, coupled with rare centromere variants, have enabled us to gain fresh insights into the linear and 3D organization of centromeric chromatin.
- Published
- 2004
221. Growth, behavior, and clinical findings in 27 patients with Kabuki (Niikawa-Kuroki) syndrome
- Author
-
K Gibson, Jane Halliday, David J. Amor, S White, Susan M. White, Agnes Bankier, Martin B. Delatycki, Alexa Kidd, Eric Haan, Anne M. Turner, Michael C Fahey, Elizabeth Thompson, Anne Baxendale, and Ravi Savarirayan
- Subjects
Adult ,Male ,Pediatrics ,medicine.medical_specialty ,Adolescent ,Birth weight ,Kabuki ,Behavioral Symptoms ,Growth ,Overweight ,Intellectual Disability ,Intellectual disability ,medicine ,Birth Weight ,Humans ,Abnormalities, Multiple ,Child ,Genetics (clinical) ,business.industry ,Australia ,Infant ,Syndrome ,medicine.disease ,Obesity ,Natural history ,Phenotype ,Child, Preschool ,Face ,Failure to thrive ,Female ,medicine.symptom ,business ,Head ,Kabuki syndrome ,New Zealand - Abstract
This study was undertaken to document the phenotype of Kabuki (Niikawa-Kuroki) syndrome in patients from Australia and New Zealand, with particular emphasis on growth patterns, behavior, and relationship between head circumference and intellectual level. Data on 27 children and adults with Kabuki (Niikawa-Kuroki) syndrome from Australia and New Zealand were collected by questionnaire and clinical assessment. The patients ranged in age from 7 months to 36 years with a mean age of 7 years and 2 months. The mean age at diagnosis was 3(5/6) years, but in most cases, the facial phenotype was evident from infancy. The minimum birth prevalence was calculated at 1 in 86,000. Three of our patients died. Parents reported a behavior phenotype characterized by an excellent long-term memory and avoidance of eye contact. No correlation was found between head circumference and severity of intellectual disability. Eight of 14 patients over the age of 5 years were overweight or obese. Six of these eight patients had failure to thrive in infancy. One patient developed insulin-dependent diabetes mellitus in adolescence. Some individuals with Kabuki (Niikawa-Kuroki) syndrome show a characteristic growth profile with failure to thrive in infancy progressing to obesity or overweight in middle childhood or adolescence. A behavior phenotype was noted which requires further investigation. Head size is not a predictor of degree of intellectual disability.
- Published
- 2004
222. Anaplastic oligodendroglioma in an adolescent with Lynch syndrome
- Author
-
Patrick Lo, Jessica Ng, Lee Coleman, John A. Heath, Victoria Beshay, and David J. Amor
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,business.industry ,nutritional and metabolic diseases ,Microsatellite instability ,Hematology ,medicine.disease ,MLH1 ,digestive system diseases ,Lynch syndrome ,MSH6 ,Germline mutation ,Oncology ,MSH2 ,Pediatrics, Perinatology and Child Health ,PMS2 ,medicine ,Cancer research ,Oligodendroglioma ,business ,neoplasms - Abstract
Lynch syndrome (hereditary non-polyposis colorectal cancer; HNPCC) is an autosomal dominant cancer predisposition syndrome with high penetrance. It is caused by heterozygous germline mutations in one of the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2. Carriers are at high-risk for developing colorectal carcinomas, as well as various extracolonic malignancies. This case report describes a 15 year-old male with a confirmed germline mutation of MSH2 and early onset anaplastic oligodendroglioma. The patient's tumor showed loss of expression of MSH2 and MSH6 proteins with normal microsatellite stability. The immunohistochemical staining pattern provided strong evidence to support the inclusion of anaplastic oligodendroglioma as part of the spectrum of tumors found in Lynch syndrome.
- Published
- 2012
223. Two further cases of Ohdo syndrome delineate the phenotypic variability of the condition
- Author
-
Susan M. White, David J. Amor, Agnes Bankier, Lesley C. Adès, Meredith Wilson, Jan Liebelt, Emma Baker, Ravi Savarirayan, and University of Groningen
- Subjects
Male ,Pediatrics ,medicine.medical_specialty ,PTOSIS ,Hearing loss ,HYPOPLASTIC TEETH ,macromolecular substances ,Blepharophimosis ,Pathology and Forensic Medicine ,Ptosis ,Intellectual Disability ,GIRL ,Intellectual disability ,medicine ,Blepharoptosis ,Humans ,OHDO SYNDROME ,Hearing Loss ,Ohdo syndrome ,Genetics (clinical) ,BLEPHAROPHIMOSIS SYNDROME ,business.industry ,FACIES ,Infant, Newborn ,Infant ,General Medicine ,medicine.disease ,Phenotype ,Hypoplasia ,HYPOTHYROIDISM ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Anatomy ,Abnormality ,medicine.symptom ,business ,MENTAL-RETARDATION - Abstract
Ohdo syndrome (MIM 249620) is a multiple malformation syndrome characterized by blepharophimosis, ptosis, dental hypoplasia, hearing impairment and intellectual disability. A wide range of dysmorphic features and congenital abnormalities have been described in cases reported as Ohdo and Ohdo-like syndromes. We report a further two cases of Ohdo syndrome, one with mild features and the other more severely affected, illustrating the phenotypic variability of the condition. A review of the literature highlights the severe phenotype associated with distinctive facial features, as seen in Case 2 in this report. All cases with the severe phenotype have been sporadic. Subtelomeric FISH studies of all chromosome arms on the two cases showed no abnormality. We propose clinical criteria for the diagnosis of Ohdo syndrome and delineate features of the severe phenotype.
- Published
- 2003
224. Familial digital arthropathy-brachydactyly
- Author
-
David J. Amor, Coral Tudball, Ravi Savarirayan, Shireen R. Lamandé, John F. Bateman, and R. J McKinlay Gardner
- Subjects
Hand deformity ,business.industry ,Brachydactyly ,ROR2 ,Anatomy ,Phalanx ,medicine.disease ,medicine.anatomical_structure ,Arthropathy ,medicine ,Deformity ,Upper limb ,Finger joint ,medicine.symptom ,business ,Genetics (clinical) - Abstract
We report a large family with a previously undescribed, dominantly inherited condition comprising arthropathy of the hands and feet and progressive shortening of the middle and distal phalanges. We have designated the condition familial digital arthropathy-brachydactyly (FDAB). Onset of FDAB is in the first decade and the arthropathy is progressive, resulting in deformity and pain in adult life. The remainder of the skeleton is not affected. It is hypothesized from the radiological appearance of patients at different ages that FDAB might result from subchondral pathology primarily affecting the heads of the phalanges, metacarpals, and metatarsals, with the arthropathy and brachydactyly being secondary effects.
- Published
- 2002
225. A protocol for whole-exome sequencing in newborns with congenital deafness: a prospective population-based cohort
- Author
-
Jane Halliday, Matthew F. Hunter, Kerryn Saunders, Melissa Wake, Elly Lynch, Valerie Sung, Zeffie Poulakis, Clara Gaff, David J. Amor, Heidi L. Rehm, Lilian Downie, Rachel A. Burt, Elizabeth Rose, Sebastian Lunke, and Melissa Martyn
- Subjects
0301 basic medicine ,Pediatrics ,medicine.medical_specialty ,Hearing loss ,Population ,Deafness ,Congenital hearing loss ,03 medical and health sciences ,0302 clinical medicine ,030225 pediatrics ,Protocol ,Genetics ,medicine ,education ,Prospective cohort study ,Exome sequencing ,education.field_of_study ,Descriptive statistics ,business.industry ,030104 developmental biology ,Pediatrics, Perinatology and Child Health ,Cohort ,Screening ,Etiology ,medicine.symptom ,business - Abstract
Introduction The aetiology of congenital hearing loss is heterogeneous, and in many infants a genetic cause is suspected. Parents face a diagnostic odyssey when searching for a cause of their infant’s hearing loss. Through the Melbourne Genomics Health Alliance, a prospective cohort of infants will be offered whole-exome sequencing (WES) with targeted analysis in conjunction with chromosome microarray to determine the genetic causes of congenital hearing loss. Parents will also be offered the opportunity to receive additional results from their infant’s WES. Methods Eligible infants will be identified through the Victorian Infant Hearing Screening Program and offered an appointment in a paediatrician-run clinic, a genetics assessment and enrolment in the Victorian Childhood Hearing Impairment Longitudinal Databank. If parents consent to WES, genes causing deafness will be analysed and they can choose to obtain additional findings. For the additional results component, a modified laboratory protocol has been designed for reporting of results in the absence of a relevant phenotype. Parents’ experience of being offered WES will be evaluated using surveys. Discussion This project will provide descriptive analysis of the genetic aetiology of congenital hearing loss in this cohort and may provide data on genotype–phenotype correlations. Additionally, choices regarding additional findings will be analysed. Participants will represent a diverse cross section of the population, increasing the ability to generalise results beyond the study group. Evaluation surveys will allow analysis of preferences around counselling, usefulness of a decision aid and adequacy of information provision.
- Published
- 2017
226. Investigating the role of somatic mutations in malformations of brain development
- Author
-
Richard J. Leventer, Paul J. Lockhart, Thomas S. Scerri, A. Simon Harvey, Duncan MacGregor, William Maixner, David J. Amor, Martin B. Delatycki, Melanie Bahlo, and Ashley P L Marsh
- Subjects
Brain development ,Somatic cell ,Biology ,Neuroscience ,Pathology and Forensic Medicine - Published
- 2017
227. Early detection of fragile X syndrome: applications of a novel approach for improved quantitative methylation analysis in venous blood and newborn blood spots
- Author
-
Xin Li, Tiffany Wotton, Danuta Z. Loesch, John L. Hopper, Michael Field, Lesley Bretherton, David E. Godler, Charles E. Schwartz, Yoshimi Inaba, David J. Amor, David Francis, Quang M. Bui, Cindy Skinner, Randi J Hagerman, and Howard R. Slater
- Subjects
Adult ,Male ,Pathology ,medicine.medical_specialty ,Adolescent ,Clinical Biochemistry ,Biology ,Methylation ,Polymerase Chain Reaction ,Sensitivity and Specificity ,Epigenesis, Genetic ,Andrology ,Cohort Studies ,Cognition ,medicine ,Humans ,Allele ,Child ,Aged ,Aged, 80 and over ,Biochemistry (medical) ,Case-control study ,Infant, Newborn ,Infant ,Venous blood ,Middle Aged ,medicine.disease ,FMR1 ,Introns ,Fragile X syndrome ,Early Diagnosis ,CpG site ,Case-Control Studies ,Child, Preschool ,Fragile X Syndrome ,DNA methylation ,Female ,Dried Blood Spot Testing - Abstract
BACKGROUND Standard fragile X syndrome (FXS) diagnostic tests that target methylation of the fragile X mental retardation 1 (FMR1) CpG island 5′ of the CGG expansion can be used to predict severity of the disease in males from birth, but not in females. METHODS We describe methylation specific–quantitative melt analysis (MS-QMA) that targets 10 CpG sites, with 9 within FMR1 intron 1, to screen for FXS from birth in both sexes. The novel method combines the qualitative strengths of high-resolution melt and the high-throughput, quantitative real-time PCR standard curve to provide accurate quantification of DNA methylation in a single assay. Its performance was assessed in 312 control (CGG RESULTS In male and female newborn blood spots, MS-QMA differentiated FM from control alleles, with sensitivity, specificity, and positive and negative predictive values between 92% and 100%. In venous blood of FM females between 6 and 35 years of age, MS-QMA correlated most strongly with verbal IQ impairment (P = 0.002). In the larger cohort of males and females, MS-QMA correlated with reference methods Southern blot and MALDI-TOF mass spectrometry (P < 0.05), but was not significantly correlated with age. Unmethylated alleles in high-functioning FM and PM males determined by both reference methods were also unmethylated by MS-QMA. CONCLUSIONS MS-QMA has an immediate application in FXS diagnostics, with a potential use of its quantitative methylation output for prognosis in both sexes.
- Published
- 2014
228. Preferences for results from genomic microarrays: comparing parents and health care providers
- Author
-
David J. Amor, Sylvia A Metcalfe, Jane Halliday, and Erin Turbitt
- Subjects
medicine.medical_specialty ,Patients ,Genetic counseling ,Health Personnel ,education ,Genetic Counseling ,Disclosure ,Statistics, Nonparametric ,Surveys and Questionnaires ,Health care ,Genetics ,Medicine ,Chromosomes, Human ,Humans ,Clinical significance ,Exome ,Genetics (clinical) ,Genetic testing ,Analysis of Variance ,medicine.diagnostic_test ,business.industry ,Australia ,Microarray Analysis ,Family medicine ,Respondent ,Medical genetics ,Personalized medicine ,business - Abstract
Chromosomal microarray (CMA) testing is now performed frequently in paediatric care. Although CMAs improve diagnostic yields, they increase detection of variants of unknown and uncertain clinical significance (VUS). Understanding parents', paediatricians' and genetic health professionals' (GHPs) views regarding variant disclosure may reduce the potential for communication of unwanted information. A questionnaire was designed to compare disclosure preferences of these three groups in Australia. One hundred and forty-seven parents, 159 paediatricians and 69 GHPs hold similar views with at least 89% of respondents certainly or probably favouring disclosure of all categories of variants. However, some differences were observed between health care providers (HCPs: paediatricians and GHPs) and parents, who were less sure of their disclosure preferences. There was consensus among respondent groups that knowledge of a variant of certain clinical significance would provide more practical and emotional utility compared to VUS. Compared to HCPs, parents placed more emphasis on using knowledge of a VUS when considering future pregnancies (p
- Published
- 2014
229. Availability of treatment drives decisions of genetic health professionals about disclosure of incidental findings
- Author
-
Erin Turbitt, Jane Halliday, David J. Amor, Sylvia A Metcalfe, and Michelle M. Wiest
- Subjects
Adult ,Male ,Adolescent ,Genetics, Medical ,Health Personnel ,Decision Making ,Short Report ,Discrete choice experiment ,ComputingMilieux_LEGALASPECTSOFCOMPUTING ,Disclosure ,Choice Behavior ,Young Adult ,Surveys and Questionnaires ,Genetics ,medicine ,Humans ,Genetic Testing ,Young adult ,Genetics (clinical) ,Genetic testing ,Incidental Findings ,medicine.diagnostic_test ,Health professionals ,business.industry ,Patient Preference ,Middle Aged ,Clinical Practice ,Clinical research ,Female ,Personalized medicine ,Age of onset ,business ,Psychology ,Clinical psychology - Abstract
Contrasting opinions exist regarding the disclosure of incidental findings detected through clinical genomic testing. This study used a discrete choice experiment to investigate genetic health professionals' preferences for the disclosure of incidental findings in an Australian paediatric setting. Four attributes of conditions relating to incidental findings were investigated: availability of prevention and treatment, chance of symptoms ever developing, age of onset and severity. Questionnaires from 59 Australian genetic health professionals were analysed. Results show that when evaluating incidental findings for disclosure, these professionals value the availability of prevention and treatment for the condition above all other characteristics included in the study. The framework of this discrete choice experiment can be used to investigate the preferences of other stakeholders such as paediatricians and parents about disclosure of incidental findings. The results of this study may be considered when assessing which categories of incidental findings are most suitable for disclosure in clinical practice.
- Published
- 2014
230. Expanding the phenotypic spectrum of ARID1B-mediated disorders and identification of altered cell-cycle dynamics due to ARID1B haploinsufficiency
- Author
-
David J. Amor, Elizabeth Fitzpatrick, Paul J. Lockhart, Kate Pope, Richard J. Leventer, Susan M. White, Anneke T. Vulto-van Silfhout, Hayley S. Mountford, Pernille Mathiesen Tørring, Shane McKee, Donna M. Muzny, Joe C H Sim, Greta Gillies, Martin B. Delatycki, Shalini N. Jhangiani, and Gabrielle R. Wilson
- Subjects
Male ,Nonsense mutation ,Micrognathism ,Intellectual disability ,Chromatin remodelling ,Haploinsufficiency ,Biology ,Cell cycle ,Frameshift mutation ,medicine ,Humans ,Genetics(clinical) ,Pharmacology (medical) ,Abnormalities, Multiple ,Coffin-Siris syndrome ,ARID1B mutation ,Coffin–Siris syndrome ,GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries) ,Genetics (clinical) ,2. Zero hunger ,Genetics ,Medicine(all) ,Research ,Cell Cycle ,General Medicine ,medicine.disease ,Chromatin Assembly and Disassembly ,Phenotype ,Human genetics ,DNA-Binding Proteins ,Face ,Female ,Neurodevelopmental disorders Radboud Institute for Molecular Life Sciences [Radboudumc 7] ,Hand Deformities, Congenital ,Neck ,Transcription Factors - Abstract
Background: Mutations in genes encoding components of the Brahma-associated factor (BAF) chromatin remodeling complex have recently been shown to contribute to multiple syndromes characterised by developmental delay and intellectual disability. ARID1B mutations have been identified as the predominant cause of Coffin-Siris syndrome and have also been shown to be a frequent cause of nonsyndromic intellectual disability. Here, we investigate the molecular basis of a patient with an overlapping but distinctive phenotype of intellectual disability, plantar fat pads and facial dysmorphism. Methods/results: High density microarray analysis of the patient demonstrated a heterozygous deletion at 6q25.3, which resulted in the loss of four genes including AT Rich Interactive Domain 1B (ARID1B). Subsequent quantitative real-time PCR analysis revealed ARID1B haploinsufficiency in the patient. Analysis of both patient-derived and ARID1B knockdown fibroblasts after serum starvation demonstrated delayed cell cycle re-entry associated with reduced cell number in the S-1 phase. Based on the patient's distinctive phenotype, we ascertained four additional patients and identified heterozygous de novo ARID1B frameshift or nonsense mutations in all of them. Conclusions: This study broadens the spectrum of ARID1B associated phenotypes by describing a distinctive phenotype including plantar fat pads but lacking the hypertrichosis or fifth nail hypoplasia associated with Coffin-Siris syndrome. We present the first direct evidence in patient-derived cells that alterations in cell cycle contribute to the underlying pathogenesis of syndromes associated with ARID1B haploinsufficiency.
- Published
- 2014
231. Parental mosaicism of JAG1 mutations in families with Alagille syndrome
- Author
-
David J. Amor, Ingo Hansmann, Joannis Giannakudis, Albrecht Röpke, Jean-Pierre Fryns, Mike Schlicker, Agnes Bankier, Annegret Kujat, Małgorzata Krajewska-Walasek, and Helen E. Hughes
- Subjects
Male ,JAG1 ,Biology ,medicine.disease_cause ,Variable Expression ,Alagille syndrome ,Genetics ,medicine ,Humans ,Serrate-Jagged Proteins ,Genetics (clinical) ,DNA Primers ,Mutation ,Base Sequence ,Mosaicism ,Calcium-Binding Proteins ,Membrane Proteins ,Proteins ,Autosomal dominant trait ,medicine.disease ,Penetrance ,Pedigree ,Alagille Syndrome ,Phenotype ,Intercellular Signaling Peptides and Proteins ,Jagged-1 Protein ,Female ,Congenital disorder - Abstract
The Alagille syndrome (AGS), a congenital disorder affecting liver, heart, skeleton and eye in association with a typical face, is an autosomal dominant disease with nearly complete penetrance and variable expression. AGS is caused by mutations in the developmentally important JAG1 gene. In our mutation screening, where 61 mutations in JAG1 were detected, we identified five cases where mosaicism is present. Our results point to a significant frequency of mosaicism for JAG1 mutations in AGS of more than 8.2%. Because mosaicism may be associated with a very mild phenotype, the appropriate diagnosis of AGS and consequently the determination of the recurrence risk can be complicated.
- Published
- 2001
232. New variant of familial cerebellar ataxia with hypergonadotropic hypogonadism and sensorineural deafness
- Author
-
David J. Amor, Elsdon Storey, Martin B. Delatycki, and R. J. M. Gardner
- Subjects
Pediatrics ,medicine.medical_specialty ,Cerebellum ,Ataxia ,Cerebellar ataxia ,business.industry ,Neurological disorder ,medicine.disease ,Central nervous system disease ,Hypergonadotropic hypogonadism ,Endocrinology ,medicine.anatomical_structure ,Internal medicine ,medicine ,Amenorrhea ,Age of onset ,medicine.symptom ,business ,Genetics (clinical) - Abstract
Cerebellar ataxia and hypergonadotropic hypogonadism comprise a rare and presumably heterogeneous association. Inheritance in most cases appears to be autosomal recessive, and associated features include deafness, intellectual impairment, and neuropathy. Typically, onset of ataxia is in the first decade and hypogonadism results in primary amenorrhoea in females. We describe two sisters with a previously undescribed pattern of adult onset progressive cerebellar ataxia and secondary amenorrhoea due to hypergonadotropic hypogonadism. Sensorineural deafness with vestibular hypofunction and peripheral sensory impairment were also present, and intellect was normal. Onset of neurological symptoms was in the third decade, with secondary amenorrhoea occurring at the ages of 16 and 32 years, respectively. The association of ataxia and hypergonadotropic hypergonadism has been classified both as a variant of Holmes type ataxia and as a variant of Perrault syndrome, but we suggest the use of a separate category of ataxia with hypergonadotropic hypogonadism.
- Published
- 2001
233. De novo 325 kb microdeletion in chromosome band 10q25.3 including ATRNL1 in a boy with cognitive impairment, autism and dysmorphic features
- Author
-
David J. Amor, Hayley S. Mountford, Zornitza Stark, Paul J. Lockhart, and D L Bruno
- Subjects
Genetics ,Ataxia ,Heterozygote advantage ,Karyotype ,General Medicine ,Biology ,medicine.disease ,Phenotype ,medicine ,Autism ,Allele ,medicine.symptom ,Gene ,Genetics (clinical) ,SNP array - Abstract
We provide the first description of a patient with a heterozygous deletion of the Attractin-like (ATRNL1) gene. The patient presented with a novel and distinctive phenotype comprising dysmorphic facial appearance, ventricular septal defect, toe syndactyly, radioulnar synostosis, postnatal growth retardation, cognitive impairment with autistic features, and ataxia. A 325 kb de novo deletion in ATRNL1 was demonstrated using SNP microarray and confirmed by FISH analysis using BAC probes. Sequence analysis of the undeleted allele did not identify any alterations, suggesting that the phenotype was the result of haploinusfficiency. ATRNL1 and its paralog ATRN are highly conserved transmembrane proteins thought to be involved in cell adhesion and signalling events. The phenotype of mice with homozygous Atrn mutations overlaps considerably with the features observed in our patient. We therefore postulate that our patient’s phenotype is caused by the deletion of ATRNL1, and provide further insight into the role of ATRNL1 in human development.
- Published
- 2010
234. Prenatally detected de novo apparently balanced chromosomal rearrangements: the effect on maternal worry, family functioning and intent of disclosure
- Author
-
Ingrid B, Sinnerbrink, Bettina, Meiser, Jane, Halliday, Amanda, Sherwen, David J, Amor, Elizabeth, Waters, Felicity, Rea, Elizabeth, Evans, Belinda, Rahman, and Edwin P, Kirk
- Subjects
Adult ,Chromosome Aberrations ,Family Health ,Male ,Mothers ,Disclosure ,Intention ,Anxiety ,Pregnancy ,Child, Preschool ,Prenatal Diagnosis ,Humans ,Female ,Genetic Testing ,Parent-Child Relations ,Child ,Stress, Psychological ,Retrospective Studies - Abstract
This study aims to assess the impact of prenatal diagnosis of de novo apparently balanced chromosome rearrangements (ABCRs) on maternal stress, family functioning and maternal plans of disclosure of genetic information to their child.All liveborn children with prenatally detected de novo ABCRs in two Australian states over a 10-year period (1994-2003) were retrospectively ascertained. Of 39 eligible cases, 16 (41%) participated in the study. Mothers of these children completed a questionnaire using standardized measures to assess family functioning, parental distress, parent-child interaction and child characteristics, with open-ended questions regarding disclosure.The majority of mothers appeared to experience normal levels of parenting stress, quality of parent-child interaction and healthy family functioning. However, most mothers recalled experiencing a significant degree of worry at the time of receiving their prenatal test results, and some mothers (4/15) reported receiving uncertain or conflicting results. Most mothers (13/15) conveyed an understanding of the importance of disclosing this genetic information to their child, and 12/15 conveyed their intention to make this disclosure.Most mothers reported normal parenting stress and family functioning, despite experiencing significant worry upon receiving results. Some children are at risk of nondisclosure of their carrier status.
- Published
- 2013
235. Comparing indicators of health and development of singleton young adults conceived with and without assisted reproductive technology
- Author
-
Jane Fisher, Lex W. Doyle, John McBain, Jane Halliday, Karin Hammarberg, Turi Berg, Robert I McLachlan, David J. Amor, Fiona Bruinsma, and Cate Wilson
- Subjects
Gerontology ,Adult ,Male ,Adolescent ,Reproductive Techniques, Assisted ,Victoria ,Offspring ,medicine.medical_treatment ,Health Status ,Body Mass Index ,Young Adult ,Quality of life ,Intervention (counseling) ,medicine ,Humans ,Young adult ,Assisted reproductive technology ,business.industry ,Obstetrics and Gynecology ,Hospitalization ,Low birth weight ,Reproductive Medicine ,Chronic Disease ,Quality of Life ,Educational Status ,Female ,medicine.symptom ,business ,Body mass index ,Cohort study - Abstract
Objective To compare outcomes for young adults conceived by assisted reproductive technology (ART) with non-ART–conceived young adults. Design Cohort study. Setting Not applicable. Participant(s) Mothers and their offspring (aged 18–28 years) conceived by ART; mothers and their non-ART–conceived offspring, randomly selected from the same source population. Intervention(s) Structured telephone interviews, one with mothers and another with their young adult offspring. Main Outcome Measure(s) Maternal report on young adult offspring hospitalizations and chronic illness accumulated over the first 18 years of their lives; young adult self-report on perceived current quality of life, body mass index, pubertal development, and educational achievement. Result(s) Of 1,480 eligible ART mothers, 80% were traced and contacted. Of those, 656 (55%) participated, reporting on 705 ART-conceived offspring; 269 (23%) declined participation and 262 (22%) did not respond. Of the participants, 84% consented to contact with their young adult offspring, of whom 547 (92%) participated. Random-digit dialing recruited 868 non-ART mothers and 549 offspring. Compared with non-ART young adults, the ART group had significant increases in three maternally reported outcomes: 1) hospital admissions, including those in the secondary school years; 2) atopic respiratory conditions; and 3) combined endocrine, nutritional, and metabolic disease ICD-10 category. Young adult reported outcomes were similar for both groups. Conclusion(s) This study addresses gaps in knowledge of outcomes beyond adolescence for those conceived by ART. Results show few adverse outcomes in this large cohort of young adults, but additional assessment through clinical review is required to address issues unable to be examined in this study.
- Published
- 2013
236. Implementation of written consent for newborn screening in Victoria, Australia
- Author
-
Taryn, Charles, James, Pitt, Jane, Halliday, and David J, Amor
- Subjects
Neonatal Screening ,Victoria ,Writing ,Practice Guidelines as Topic ,Infant, Newborn ,Humans ,Parental Consent ,Guideline Adherence ,Quality Improvement - Abstract
There has been increasing evidence of a lack of public awareness of newborn screening and concern about inadequate consent being obtained from parents. Apprehension also exists in relation to storage and secondary use of screening samples. Our objective was to introduce a written consent process across Victoria as a means of strengthening programme transparency, quality and supporting parental choice. In addition, more comprehensive information covering all aspects of the programme was developed.A 'two-stage' written consent protocol allowed parents to give separate consent for (i) their baby to be screened and (ii) secondary use of the sample in de-identified health research. At the time of sample collection, parents were asked to complete the consent form, included as part of the screening card. The protocol was piloted in four public hospitals and subsequently implemented statewide.Twelve months of laboratory data showed that although refusals for screening increased, overall participation remained above 99%. The percentage of parents opting out of research use was 6.5%. Provider compliance with the new protocol was high, with only 1.4% of cards received without a completed consent form.This quality improvement project has demonstrated that parents can participate more fully in newborn screening without jeopardising high uptake. As a secondary benefit, the public health resource of stored cards can be maintained with parental support. Future work needs to examine the quality of consent being given by parents and investigation of the reasons why some choose to decline.
- Published
- 2013
237. New case of Cole-Carpenter syndrome
- Author
-
David J. Amor, Agnes Bankier, Ravi Savarirayan, and Adele Schneider
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,business.industry ,Dysostosis ,Anatomy ,medicine.disease ,Osteochondrodysplasia ,Craniosynostosis ,Developmental disorder ,Frontal Bossing ,Osteogenesis imperfecta ,medicine ,Craniofacial ,business ,Cole Carpenter syndrome ,Genetics (clinical) - Abstract
We describe a girl with a severe progressive type of osteogenesis imperfecta, in association with multisutural craniosynostosis, growth failure, and craniofacial findings including ocular proptosis, marked frontal bossing, midface hypoplasia, and micrognathia. Collagen analysis was normal. These features are consistent with the diagnosis of Cole-Carpenter syndrome. This report provides further evidence for the existence of this rare genetic entity.
- Published
- 2000
238. Polymicrogyria associated with scalp and limb defects: Variant of Adams-Oliver syndrome
- Author
-
David J. Amor, Richard J. Leventer, Sari Hayllar, and Agnes Bankier
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Psychomotor retardation ,business.industry ,Anatomy ,Aplasia ,Consanguinity ,medicine.disease ,Aplasia cutis congenita ,Congenital lymphedema ,body regions ,Endocrinology ,medicine.anatomical_structure ,Scalp ,Internal medicine ,Polymicrogyria ,Medicine ,medicine.symptom ,business ,Genetics (clinical) ,Adams–Oliver syndrome - Abstract
We describe cortical malformations in two siblings who also had features of Adams-Oliver syndrome (AOS, MIM 100300). The parents were first cousins and showed no signs of either disorder, suggesting autosomal recessive inheritance. Psychomotor delay was present in both sibs, and cerebral imaging was indicative of polymicrogyria (PMG). One sib had aplasia cutis congenita of the scalp and transverse limb defects, and the other had short fingers and toes and also developed lymphedema of the right leg. CNS abnormalities and lymphatic abnormalities are rare manifestations of AOS, and we suggest that these sibs have a rare variant of AOS with probable recessive inheritance.
- Published
- 2000
239. Analysis of CDKN1C in Beckwith Wiedemann Syndrome
- Author
-
Samantha Brickell, David J. Amor, Peter J. Smith, Elizabeth M. Algar, and Gillian J Deeble
- Subjects
Genetics ,Beckwith–Wiedemann syndrome ,Locus (genetics) ,Biology ,medicine.disease ,Molecular biology ,Phenotype ,medicine ,Coding region ,Allele ,Imprinting (psychology) ,Genomic imprinting ,Gene ,Genetics (clinical) - Abstract
In this study we have examined 32 patients with Beckwith Wiedemann Syndrome (BWS) for mutations affecting the CDKN1C gene, including seven cases of familial BWS. Mutations were not detected in the coding region of the CDKN1C gene in any individual with BWS. However in two patients, two G/A base substitutions at adjacent positions in the 5'UTR were detected. These substitutions were also found in normal controls. Expression of CDKN1C in somatic tissues was examined in 18 of the 32 cases using semi-quantitative RT-PCR. CDKN1C expression was significantly reduced in the peripheral blood of three cases compared with controls. These results suggest that, although coding region mutations in the CDKN1C gene are rare in BWS, mutations disrupting CDKN1C expression may be found. Three of five informative patients exhibited biallelic CDKN1C expression in lymphocytes, cord blood, and kidney tissue, respectively. Biallelic expression was not associated with overall CDKN1C levels significantly different to those in controls. Patients who expressed CDKN1C biallelically, or who were low CDKN1C expressors, maintained monoallelic methylation in the Differentially Methylated Region 2 (DMR2) of the IGF2 locus. One patient expressing CDKN1C biallelically, maintained imprinted gene expression at the IGF2 locus. These results suggest that biallelic CDKN1C expression does not significantly perturb the overall levels of CDKN1C expression in somatic tissue. They also confirm other studies showing that the mechanisms associated with regulating CDKN1C expression and imprinting are separate from those regulating IGF2 imprinting.
- Published
- 2000
240. Familial upper eyelid coloboma with ipsilateral anterior hairline abnormality: Two new reports of MOTA syndrome
- Author
-
Alison Yeung, Ravi Savarirayan, and David J. Amor
- Subjects
Male ,Cryptophthalmos ,Craniofacial abnormality ,Population ,Craniofacial Abnormalities ,Anterior hairline ,Genetics ,medicine ,Humans ,Abnormalities, Multiple ,Hypertelorism ,Craniofacial ,education ,Genetics (clinical) ,Coloboma ,education.field_of_study ,business.industry ,Infant, Newborn ,Eyelids ,Infant ,Syndrome ,Anatomy ,medicine.disease ,Pedigree ,Phenotype ,medicine.anatomical_structure ,Child, Preschool ,Female ,Eyelid ,medicine.symptom ,business ,Hair - Abstract
We describe two patients with upper eyelid coloboma, hypertelorism, disruption of the eyebrow, and anterior hairline anomaly. The phenotype in our patients is consistent with Manitoba Oculotrichoanal syndrome (MOTA syndrome, OMIM 248450), which comprises a variable spectrum of eyelid malformations ranging from cryptophthalmos to upper eyelid colobomas; aberrant ipsilateral anterior hairline, and anal anomalies. It was first described in members of the indigenous population of the Island Lake region of Northern Manitoba, Canada. Autosomal recessive inheritance is demonstrated in these families and single-gene etiology has been proposed. This constellation of anomalies also corresponds to those arising from the Number 10 cleft in Tessier's anatomical classification of clefting malformations. Tessier Number 10 clefts are the rarest of the 15 craniofacial clefting malformations first described by Tessier [Tessier (1976); J Maxillofac Surg 4:69-92]. They have only ever been reported as sporadic occurrences and the underlying etiology is thought to be environmental. We believe the phenotype in our patients and in those previously described with MOTA syndrome represents a disorder of craniofacial clefting; specifically, one that occurs along the tissue planes of the Tessier Number 10 cleft. The familial clustering of these facial features and their variable association with other congenital anomalies supports a genetic rather than environmental cause. The mapping of the gene for this syndrome is likely to involve a combined functional and positional approach with a focus on candidate genes involved in craniofacial development.
- Published
- 2009
241. Recurrence risk in Autism Spectrum Disorder: A study of parental knowledge
- Author
-
Peter Flett, David J. Amor, and Charlotte Whitelaw
- Subjects
Adult ,Parents ,Health Knowledge, Attitudes, Practice ,medicine.medical_specialty ,Genetic counseling ,Genetic Counseling ,Risk Assessment ,Tasmania ,Recurrence risk ,Interviews as Topic ,Risk Factors ,Health care ,medicine ,Humans ,Genetic Predisposition to Disease ,Asperger Syndrome ,Autistic Disorder ,Child ,Psychiatry ,Parental knowledge ,Health Education ,business.industry ,medicine.disease ,Telephone interview ,Child Development Disorders, Pervasive ,Autism spectrum disorder ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Autism ,business - Abstract
Aim: To describe recurrence risk information currently being obtained by families affected by Autism Spectrum Disorder (ASD). Methods: Structured telephone interview of parents of 21 children who received a diagnosis of ASD at Calvary Health Care Tasmania, Hobart, Australia between May 2005 and May 2006. Results: Only one of the 21 parents knew their true recurrence risk. Many overestimated their risk substantially, and in four cases this had led to a decision against increasing family size. Eleven parents said they had received no information about recurrence risk, and only one cited medical practitioners as a source of information about recurrence risk. Conclusion: Current provision of information about recurrence risk to families affected by ASD is inadequate.
- Published
- 2007
242. Fertility in Turner syndrome
- Author
-
Yasmin Jayasinghe, Sonia Grover, Lynn Gillam, Garry L. Warne, Jacqueline K. Hewitt, Margaret Zacharin, and David J. Amor
- Subjects
Infertility ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,media_common.quotation_subject ,Turner Syndrome ,Fertility ,Reproductive technology ,Endocrinology ,Ovarian Follicle ,medicine ,Animals ,Humans ,Ovarian tissue cryopreservation ,Fertility preservation ,media_common ,Cryopreservation ,Gynecology ,Pregnancy ,business.industry ,Obstetrics ,medicine.disease ,Transplantation ,Oocytes ,Female ,business ,Live birth - Abstract
There is increasing interest in fertility and use of assisted reproductive technologies for women with Turner syndrome (TS). Current parenting options include adoption, surrogacy, and spontaneous and assisted reproduction. For women with TS, specific risks of pregnancy include higher than usual rates of spontaneous abortion, foetal anomaly, maternal morbidity and mortality. Heterologous fertility assistance using oocytes from related or unrelated donors is an established technique for women with TS. Homologous fertility preservation includes cryopreservation of the patient's own gametes prior to the progressive ovarian atresia known to occur: preserving either mature oocytes or ovarian tissue containing primordial follicles. Mature oocyte cryopreservation requires ovarian stimulation and can be performed only in postpubertal individuals, when few women with TS have viable oocytes. Ovarian tissue cryopreservation, however, can be performed in younger girls prior to ovarian atresia - over 30 pregnancies have resulted using this technique, however, none in women with TS. We recommend consideration of homologous fertility preservation techniques in children only within specialized centres, with informed consent using protocols approved by a research or clinical ethics board. It is essential that further research is performed to improve maternal and foetal outcomes for women with TS.
- Published
- 2013
243. Relationships between age and epi-genotype of the FMR1 exon 1/intron 1 boundary are consistent with non-random X-chromosome inactivation in FM individuals, with the selection for the unmethylated state being most significant between birth and puberty
- Author
-
David J. Amor, David Francis, Howard R. Slater, Elva Z. Shi, Randi J Hagerman, Charles E. Schwartz, Yoshimi Inaba, Quang M. Bui, Cindy Skinner, Danuta Z. Loesch, John L. Hopper, and David E. Godler
- Subjects
Adult ,Male ,medicine.medical_specialty ,congenital, hereditary, and neonatal diseases and abnormalities ,Adolescent ,Biology ,Methylation ,X-inactivation ,Epigenesis, Genetic ,Exon ,Fragile X Mental Retardation Protein ,X Chromosome Inactivation ,Internal medicine ,Genetics ,medicine ,Humans ,Allele ,Child ,Molecular Biology ,Genetics (clinical) ,X chromosome ,Aged ,Aged, 80 and over ,Age Factors ,Infant, Newborn ,Infant ,RNA-Binding Proteins ,General Medicine ,Exons ,Articles ,Middle Aged ,medicine.disease ,FMR1 ,Fragile X syndrome ,Endocrinology ,CpG site ,Child, Preschool ,Fragile X Syndrome ,Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ,Mutation ,CpG Islands ,Female - Abstract
Methylation of the fragile X-related epigenetic element 2 (FREE2) located on the exon 1/intron 1 boundary of the FMR1 gene is related to FMRP expression and cognitive impairment in full mutation (FM; CGG>200) individuals. We examined the relationship between age, the size of the FMR1 CGG expansion and the methylation output ratio (MOR) at 12 CpG sites proximal to the exon 1/intron 1 boundary using FREE2 MALDI-TOF MS. The patient cohort included 119 males and 368 females, i.e. 121 healthy controls (CGG
- Published
- 2013
244. New ZMPSTE24 (FACE1) mutations in patients affected with restrictive dermopathy or related progeroid syndromes and mutation update
- Author
-
Thuy Duong Nguyen, Manfred Wehnert, Valérie Cormier-Daire, Peter Meinke, Catherine Badens, Annachiara De Sandre-Giovannoli, Le Thi Thanh Huong, Nicolas Lévy, Winnie Schröder, Amandine Boyer, Patrice Roll, Kristina Lagerstedt, Pierre Cau, Vera Esteves-Vieira, David J. Amor, Martine Biervliet, Peter C. van den Akker, Yves Sznajer, Claire Navarro, Sébastien Courrier, Aix Marseille Université (AMU), Génétique Médicale et Génomique Fonctionnelle (GMGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie Cellulaire [Hôpital de la Timone - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Hôpital de la Timone [CHU - APHM] (TIMONE), Université Grenoble Alpes - UFR Pharmacie (UGA UFRP), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Ernst-Moritz-Arndt-Universität Greifswald, Vietnam Academy of Science and Technology (VAST), University of Edinburgh, Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cliniques Universitaires Saint-Luc [Bruxelles], Murdoch Children's Research Institute (MCRI), Karolinska University Hospital [Stockholm], Antwerp University Hospital [Edegem] (UZA), University Medical Center Groningen [Groningen] (UMCG), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de référence maladie rare Thalassémie, Centre de ressources biologiques Tissus ADN Cellules [Hôpital de la Timone - APHM] (CRB TAC), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Surgical clinical sciences, Clinical sciences, Translational Immunology Groningen (TRIGR), UCL - SSS/IREC - Institut de recherche expérimentale et clinique, UCL - (SLuc) Centre de génétique médicale UCL, and ROLL, Patrice
- Subjects
Male ,DNA Mutational Analysis ,LAMINOPATHIES ,[SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC] ,PHENOTYPE ,Compound heterozygosity ,MANDIBULOACRAL DYSPLASIA ,Progeroid syndromes ,Progeria ,PRELAMIN-A ,NUCLEAR-ENVELOPE ,LAMIN-A ,Genetics (clinical) ,Genetics ,Fetal Growth Retardation ,Research Support, Non-U.S. Gov't ,ZMPSTE24 ,Metalloendopeptidases ,Exons ,Founder Effect ,Pedigree ,3. Good health ,Chemistry ,Female ,Haploinsufficiency ,Contracture ,progeroid syndromes ,[SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics ,Biology ,restrictive dermopathy ,Article ,HUTCHINSON-GILFORD PROGERIA ,prelamin A maturation ,2 SIBLINGS ,[SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC] ,medicine ,Humans ,Allele ,Mandibulo-acral dysplasia ,INTERMEDIATE-FILAMENT PROTEINS ,Alleles ,Genetic Association Studies ,Genodermatosis ,Membrane Proteins ,[SDV.MHEP.DERM] Life Sciences [q-bio]/Human health and pathology/Dermatology ,medicine.disease ,GENE ,Introns ,Mandibuloacral dysplasia ,Amino Acid Substitution ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,Mutation ,Skin Abnormalities ,Human medicine ,RNA Splice Sites ,Restrictive dermopathy ,[SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology - Abstract
Restrictive dermopathy (RD) is a rare and extremely severe congenital genodermatosis, characterized by a tight rigid skin with erosions at flexure sites, multiple joint contractures, low bone density and pulmonary insufficiency generally leading to death in the perinatal period. RD is caused in most patients by compound heterozygous or homozygous ZMPSTE24 null mutations. This gene encodes a metalloprotease specifically involved in lamin A post-translational processing. Here, we report a total of 16 families for whom diagnosis and molecular defects were clearly established. Among them, we report seven new ZMPSTE24 mutations, identified in classical RD or Mandibulo-acral dysplasia (MAD) affected patients. We also report nine families with one or two affected children carrying the common, homozygous thymine insertion in exon 9 and demonstrate the lack of a founder effect. In addition, we describe several new ZMPSTE24 variants identified in unaffected controls or in patients affected with non-classical progeroid syndromes. In addition, this mutation update includes a comprehensive search of the literature on previously described ZMPSTE24 mutations and associated phenotypes. Our comprehensive analysis of the molecular pathology supported the general rule: complete loss-of-function of ZMPSTE24 leads to RD, whereas other less severe phenotypes are associated with at least one haploinsufficient allele. © 2014 Macmillan Publishers Limited All rights reserved.
- Published
- 2013
245. Beckwith-Wiedemann Syndrome and IVF: A Case-Control Study
- Author
-
David J. Amor, Elizabeth M. Algar, Jane Halliday, Sue Breheny, and Kay Oke
- Subjects
Male ,Risk ,medicine.medical_specialty ,Beckwith-Wiedemann Syndrome ,medicine.medical_treatment ,Population ,Prenatal diagnosis ,Fertilization in Vitro ,Intracytoplasmic sperm injection ,Genomic Imprinting ,Pregnancy ,Genetics ,Humans ,Medicine ,Genetics(clinical) ,Gamete intrafallopian transfer ,education ,Letter to the Editor ,Genetics (clinical) ,Retrospective Studies ,education.field_of_study ,business.industry ,Obstetrics ,Odds ratio ,medicine.disease ,Oligospermia ,Case-Control Studies ,Female ,business ,Record linkage - Abstract
To the Editor: A recent series of observations has suggested a linkbetween in vitro fertilization (IVF) and imprinting disorders, such as Beckwith-Wiedemann syndrome (BWS [MIM 130650]) and Angelman syndrome (MIM 105830). BWS is a model imprinting disorder and is characterized by prenatal and/or postnatal overgrowth, macroglossia, abdominal-wall defects, neonatal hypoglycemia, hemihypertrophy, ear abnormalities, and an increased risk of embryonal tumors (DeBaun et al. 2002). An analysis of BWS registries from three centers has shown the proportion of individuals with BWS conceived using IVF to be 3/65 (DeBaun et al. 2003), 6/149 (Maher et al. 2003), and 6/149 (Gicquel et al. 2003). These data suggest that ∼4% of individuals with BWS are conceived using IVF, a figure greater than the generally accepted usage of IVF in these centers. Further interpretation of these results has been limited because of a reliance by these studies on case records and questionnaire data to determine the method of conception in BWS cases, a lack of the use of appropriate controls, and a statistical significance that was either borderline (Gicquel et al. 2003; Maher et al. 2003) or not mentioned (DeBaun et al. 2003). A recent review of the epidemiology and molecular biology behind these and other related studies has highlighted the need for case-control studies in this area (Niemitz and Feinberg 2004). We report here the results of what we believe is the first case-control study done to test the null hypothesis that there is no difference between the rate of IVF in BWS cases and that in non-BWS controls, in an Australian population. The present study was possible because the State of Victoria, Australia, is serviced by a single clinical genetics service and laboratory providing molecular tests for BWS. This allowed complete ascertainment of children born in Victoria between 1983 and 2003 and diagnosed with BWS by a clinical geneticist. Only cases meeting the DeBaun criteria (DeBaun and Tucker 1998) were included in this study. Appropriate controls were obtained using data from the Victorian Perinatal Data Collection Unit, which registers all births of >19-wk gestation. For each BWS case, four live-born controls were randomly selected from babies born within 1 mo of that case, in which parity was 1 and the maternal age was within 1 year of the risk-set case. Manual record linkage was then used to determine if the BWS cases and the controls were recorded in the databases of the providers of IVF services in Victoria, with the use of maternal names and the dates of birth of mothers and babies. Ethics approval was obtained from all sites providing data. Statistical significance of differences in proportions between groups was assessed using Epi Info, with results expressed as odds ratios (ORs) and as Fisher's-exact-test two-sided P values to account for cell sizes
- Published
- 2004
246. Health and development of ART conceived young adults: a study protocol for the follow-up of a cohort
- Author
-
David J. Amor, Karin Hammarberg, Jane Fisher, Turi Berg, Fiona Bruinsma, Cate Wilson, Ann Sanson, and Jane Halliday
- Subjects
Gerontology ,Male ,medicine.medical_treatment ,Health Status ,Reproductive technology ,Study Protocol ,Psychological adjustment ,0302 clinical medicine ,Child Development ,Clinical Protocols ,In vitro fertilization ,Obstetrics and Gynaecology ,030212 general & internal medicine ,Parent-Child Relations ,Child ,media_common ,Daughter ,education.field_of_study ,030219 obstetrics & reproductive medicine ,Follow-up ,Obstetrics and Gynecology ,Assisted reproductive technology ,Research Design ,Health ,Educational Status ,Female ,Psychosocial ,Adult ,medicine.medical_specialty ,Adolescent ,Psychometrics ,Reproductive Techniques, Assisted ,media_common.quotation_subject ,Population ,Development ,03 medical and health sciences ,Young Adult ,medicine ,Humans ,Ethics, Medical ,Psychiatry ,education ,Retrospective Studies ,business.industry ,Public health ,Patient Selection ,Child development ,Reproductive Medicine ,Telephone interview ,Quality of Life ,business ,Follow-Up Studies - Abstract
Background Use of assisted reproductive technologies (ART) continues to increase, yet little is known of the longer term health of ART conceived offspring. There are some adverse birth outcomes associated with ART conception but the subsequent developmental trajectory is unclear. Undertaking research in this area is challenging due the sensitive nature of the topic and the time elapsed since birth of the ART conceived young adults. The aim of this report is to describe a research protocol, including design and ethical considerations, used to compare the physical and psychosocial health outcomes of ART conceived young adults aged 18-28 years, with their spontaneously conceived peers. Design This is a retrospective cohort study of mothers who conceived with ART in Victoria, Australia and gave birth to a singleton child between 1982 and 1992. A current address for each mother was located and a letter of invitation to participate in the study was sent by registered mail. Participation involved completing a telephone interview about her young adult offspring’s health and development from birth to the present. Mothers were also asked for consent for the researcher to contact their son/daughter to invite them to complete a structured telephone interview about their physical and psychosocial health. A comparison group of women living in Victoria, Australia, who had given birth to a spontaneously conceived singleton child between 1982 and 1992 was recruited from the general population using random digit dialling. Data were collected from them and their young adult offspring in the same way. Regression analyses were used to evaluate relationships between ART exposure and health status, including birth defects, chronic health conditions, hospital admissions, growth and sexual development. Psychosocial wellbeing, parental relationships and educational achievement were also assessed. Factors associated with the age of disclosure of ART conception were explored with the ART group only. Discussion The conceptualization and development of this large project posed a number of methodological, logistical and ethical challenges which we were able to overcome. The lessons we learnt can assist others who are investigating the long-term health implications for ART conceived offspring.
- Published
- 2012
247. Long-term health and development of children diagnosed prenatally with a de novo apparently balanced chromosomal rearrangement
- Author
-
Ingrid B, Sinnerbrink, Amanda, Sherwen, Bettina, Meiser, Jane, Halliday, David J, Amor, Elizabeth, Waters, Felicity, Rea, Elizabeth, Evans, Belinda, Rahman, and Edwin P, Kirk
- Subjects
Adult ,Chromosome Aberrations ,Adolescent ,Infant, Newborn ,Pregnancy Outcome ,Translocation, Genetic ,Child Development ,Health ,Pregnancy ,Child, Preschool ,Prenatal Diagnosis ,Humans ,Female ,Child ,Retrospective Studies - Abstract
This study aimed to determine if liveborn children with prenatally detected de novo apparently balanced chromosome rearrangements (ABCR) have more long-term health, developmental or behavioural concerns compared with children in a normal Australian population.This was a retrospective ascertainment of all liveborn children with prenatally detected de novo ABCRs in two Australian states over a 10-year period (1994-2003). Child health, development and behaviour were assessed by maternal report using standardised measures; educational ability and achievement were measured by direct child assessment. Data were compared with relevant population norms, and one sample t-test performed to test for statistical differences.Of 39 eligible cases, 16 (41%) participated in the study. One child (6%) was born with a congenital anomaly, and two children (12.5%) reported a chronic health concern. Compared with population norms, no significant differences were observed with respect to intelligence, mental health, child development and educational ability; children had significantly higher scores indicative of better functioning on bodily pain, social-emotional behaviour and physical functioning. No child satisfied the criteria for having a special health care need.Children in this study with a prenatally detected de novo ABCR have similar long-term health, developmental and behavioural outcomes compared with population norms.
- Published
- 2012
248. Meeting the challenge of interpreting high-resolution single nucleotide polymorphism array data in prenatal diagnosis: does increased diagnostic power outweigh the dilemma of rare variants?
- Author
-
Ricardo Palma-Dias, Devika Ganesamoorthy, David J. Amor, C Ngo, Fiona Norris, Pertile, Ralph Oertel, Susan M. White, Susan P. Walker, George McGillivray, Alison Yeung, P. Charan, Howard R. Slater, AR Arvaj, S Adroub, Nicole Woodrow, and Damien L. Bruno
- Subjects
Pediatrics ,medicine.medical_specialty ,DNA Copy Number Variations ,Population ,Cell Culture Techniques ,Single-nucleotide polymorphism ,Prenatal diagnosis ,Bioinformatics ,Polymorphism, Single Nucleotide ,Ultrasonography, Prenatal ,Obstetrics and gynaecology ,Pregnancy ,Prenatal Diagnosis ,medicine ,Humans ,Clinical significance ,Copy-number variation ,Prospective Studies ,education ,Oligonucleotide Array Sequence Analysis ,education.field_of_study ,business.industry ,Obstetrics and Gynecology ,Uniparental Disomy ,medicine.disease ,Uniparental disomy ,Karyotyping ,Medical genetics ,Female ,business - Abstract
Objective Several studies have already shown the superiority of chromosomal microarray analysis (CMA) compared with conventional karyotyping for prenatal investigation of fetal ultrasound abnormality. This study used very high-resolution single nucleotide polymorphism (SNP) arrays to determine the impact on detection rates of all clinical categories of copy number variations (CNVs), and address the issue of interpreting and communicating findings of uncertain or unknown clinical significance, which are to be expected at higher frequency when using very high-resolution CMA. Design Prospective validation study. Setting Tertiary clinical genetics centre. Population Women referred for further investigation of fetal ultrasound anomaly. Methods We prospectively tested 104 prenatal samples using both conventional karyotyping and high-resolution arrays. Main outcome measures The detection rates for each clinical category of CNV. Results Unequivocal pathogenic CNVs were found in six cases, including one with uniparental disomy (paternal UPD 14). A further four cases had a 'likely pathogenic' finding. Overall, CMA improved the detection of 'pathogenic' and 'likely pathogenic' abnormalities from 2.9% (3/104) to 9.6% (10/104). CNVs of 'unknown' clinical significance that presented interpretational difficulties beyond results from parental investigations were detected in 6.7% (7/104) of samples. Conclusions Increased detection sensitivity appears to be the main benefit of high-resolution CMA. Despite this, in this cohort there was no significant benefit in terms of improving detection of small pathogenic CNVs. A potential disadvantage is the high detection rate of CNVs of 'unknown' clinical significance. These findings emphasise the importance of establishing an evidence-based policy for the interpretation and reporting of CNVs, and the need to provide appropriate pre- and post-test counselling. © 2013 The Authors BJOG An International Journal of Obstetrics and Gynaecology
- Published
- 2012
249. Fragile X-related element 2 methylation analysis may provide a suitable option for inclusion of fragile X syndrome and/or sex chromosome aneuploidy into newborn screening: a technical validation study
- Author
-
Charles E. Schwartz, Quang M. Bui, Cindy Skinner, Elva Z. Shi, Danuta Z. Loesch, Jacqueline K. Hewitt, David E. Godler, Yoshimi Inaba, Alison Arvaj, Jonathon Cohen, Randi J Hagerman, Sylvia A Metcalfe, Howard R. Slater, Joanna E. Cobb, Amy S Herlihy, Tiffany Wotton, David Francis, John L. Hopper, Kate Pope, and David J. Amor
- Subjects
Adult ,Male ,Adolescent ,Gene Dosage ,Aneuploidy ,Biology ,Sensitivity and Specificity ,Cell Line ,Fragile X Mental Retardation Protein ,Young Adult ,Neonatal Screening ,medicine ,Humans ,Genetic Testing ,Allele ,Genes, sry ,Child ,Genetics (clinical) ,Alleles ,Sex Chromosome Aberrations ,Aged ,Genetics ,Newborn screening ,Infant, Newborn ,Infant ,Reproducibility of Results ,Karyotype ,DNA Methylation ,Middle Aged ,medicine.disease ,FMR1 ,Introns ,Fragile X syndrome ,Testis determining factor ,Child, Preschool ,Fragile X Syndrome ,CpG Islands ,Female ,Klinefelter syndrome ,Trinucleotide Repeat Expansion - Abstract
We show that a novel fragile X–related epigenetic element 2 FMR1 methylation test can be used along with a test for sex-determining region Y (SRY) to provide the option of combined fragile X syndrome and sex chromosome aneuploidy newborn screening. Fragile X–related epigenetic element 2, SRY, and FMR1 CGG repeat analyses were performed on blood and saliva DNA, and in adult and newborn blood spots. The cohort consisted of 159 controls (CGG
- Published
- 2012
250. 14q12 and severe Rett-like phenotypes: new clinical insights and physical mapping of FOXG1-regulatory elements
- Author
-
David J. Amor, Patrick Edery, Aissa Moustaïne, Michael Harbord, Philippe Jonveaux, Elizabeth Thompson, Christophe Nemos, Adeline Vigouroux, Aline Saunier, Eric Bieth, Christophe Philippe, Anne Destrée, Daniel Amsallem, Lila Allou, François Rivier, Julian Nicholl, and Laetitia Lambert
- Subjects
Male ,Microcephaly ,DNA Copy Number Variations ,Transcription, Genetic ,FOXG1 Gene ,Rett syndrome ,Locus (genetics) ,Nerve Tissue Proteins ,Postnatal microcephaly ,Biology ,Bioinformatics ,Article ,Cell Line ,Dysgenesis ,Intellectual Disability ,Genetics ,medicine ,Rett Syndrome ,Silencer Elements, Transcriptional ,Humans ,Point Mutation ,Child ,Genetics (clinical) ,Protein Kinase C ,Chromosomes, Human, Pair 14 ,Dyskinesias ,Forkhead Transcription Factors ,Syndrome ,medicine.disease ,Physical Chromosome Mapping ,FOXG1 ,Phenotype ,Child, Preschool ,Female ,Agenesis of Corpus Callosum ,Gene Deletion ,Forkhead Box Protein G1 - Abstract
The Forkhead box G1 (FOXG1) gene has been implicated in severe Rett-like phenotypes. It encodes the Forkhead box protein G1, a winged-helix transcriptional repressor critical for forebrain development. Recently, the core FOXG1 syndrome was defined as postnatal microcephaly, severe mental retardation, absent language, dyskinesia, and dysgenesis of the corpus callosum. We present seven additional patients with a severe Rett-like neurodevelopment disorder associated with de novo FOXG1 point mutations (two cases) or 14q12 deletions (five cases). We expand the mutational spectrum in patients with FOXG1-related encephalopathies and precise the core FOXG1 syndrome phenotype. Dysgenesis of the corpus callosum and dyskinesia are not always present in FOXG1-mutated patients. We believe that the FOXG1 gene should be considered in severely mentally retarded patients (no speech-language) with severe acquired microcephaly (−4 to−6 SD) and few clinical features suggestive of Rett syndrome. Interestingly enough, three 14q12 deletions that do not include the FOXG1 gene are associated with phenotypes very reminiscent to that of FOXG1-mutation-positive patients. We physically mapped a putative long-range FOXG1-regulatory element in a 0.43 Mb DNA segment encompassing the PRKD1 locus. In fibroblast cells, a cis-acting regulatory sequence located more than 0.6 Mb away from FOXG1 acts as a silencer at the transcriptional level. These data are important for clinicians and for molecular biologists involved in the management of patients with severe encephalopathies compatible with a FOXG1-related phenotype.
- Published
- 2012
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.