Search

A severe expression of the Greig polysyndactyly-craniofacial dysmorphism syndrome is reported in two dizygotic 4-month-old twin brothers. A minor expression of this autosomal dominant syndrome was present in the father. [ABSTRACT FROM AUTHOR]

In a retrospective study, peripheral blood mononuclear cells from 13 patients with known ataxia telangiectasia (AT) (Louis Bar syndrome, McKusick #20890) were irradiated with different doses of X-rays prior to stimulation with phytohaemagglutinin. Mitogen response and cell cycle progression were assessed by two-parameter 5-bromo-2'-deoxyuridine/Hoechst--ethidium bromide flow cytometry. Compared to age-matched controls, AT cells show a severely defective mitogen response in both unirradiated and irradiated cells. Following irradiation with 1.5 Gy, AT cells exhibit significantly greater accumulations of cells in the G2 phase of the first cell cycle than controls. The ratio between the number of cells accumulated in the first cycle G2 phase and the growth fraction provides a clear distinction between AT and control cultures. In addition, two patients with microcephaly, normal intelligence, immunodeficiency, chromosomal instability and risk for lymphoreticular malignancies (Seemanová syndrome) and two patients with the Nijmegen breakage syndrome (both syndromes are listed as McKusick #25126) also exhibit very poor mitogen response and moderately increased G2 phase accumulations after X-irradiation. The simultaneous assessment of radiosensitivity and mitogen response in a single cell kinetic assay provides a speedy and accurate classification of cells of AT and AT-related syndromes. [ABSTRACT FROM AUTHOR]

ABSTRACT Objective Congenital diaphragmatic hernia (CDH) is a fetal abnormality affecting diaphragm and lung development with a high mortality rate despite advances in fetal and neonatal therapy. CDH may occur either as an isolated defect or in syndromic form for which the prognosis is worse. Although conventional karyotyping and, more recently, chromosomal microarrays support a substantial role for genetic factors, causal genes responsible for isolated CDH remain elusive. We propose that chromosomal microarray analysis will identify copy number variations (CNVs) associated with isolated CDH. Methods We perform a prospective genome-wide screen for CNVs using chromosomal microarrays on 75 fetuses referred with apparently isolated CDH, six of which were later reclassified as non-isolated CDH. Results The results pinpoint haploinsufficiency of NR2F2 as a cause of CDH and cardiovascular malformations. In addition, the 15q25.2 and 16p11.2 recurrent microdeletions are associated with isolated CDH. By using gene prioritisation and network analysis, we provide strong evidence for several novel dosage-sensitive candidate genes associated with CDH. Conclusions Chromosomal microarray analysis detects submicroscopic CNVs associated with isolated CDH or CDH with cardiovascular malformations. © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Chabchoub E, Willekens D, Vermeesch JR, Fryns J-P. Holoprosencephaly and ZIC2 microdeletions: novel clinical and epidemiological specificities delineated. Holoprosencephaly (HPE), the most common malformation of the human brain results from abnormal cleavage of the forebrain during the early embryonic developmental stages. The spectrum of malformations in HPE is wide, ranging from the classical cyclopia/proboscis to fairly asymptomatic forms [i.e. a single maxillary central incisor (SMCI)]. HPE may be caused by environmental or genetic factors. ZIC2 (13q32) was the second gene identified in which mutations cause HPE and recently a specific phenotype was ascribed to ZIC2-mutation HPE. Earlier, we reported a boy presenting HPE and deafness. Cytogenetic analyses were normal. Using array-comparative genomic hybridization (aCGH), we found a de novo 129 kb del(13)(q32) encompassing ZIC2 and ZIC5. There is no evidence for the involvement of ZIC5 in human diseases. We reviewed the literature for ZIC2- ZIC5 deletions and their involvement in neural tube defects (NTDs). Interestingly, we found evidence for a specific facial phenotype for ZIC2 gene deletion patients distinct from those with point mutations. In addition, based on the clinical data together with pathology, imaging and functional studies, we suggest an outline for a model explaining the genetic heterogeneity of ZIC2- ZIC5-associated NTDs and propose further studies for validation. [ABSTRACT FROM AUTHOR]

Background: In 1967, Cross et al. [J Pediatr 1967;70:398-406] reported four siblings with intellectual disability, microcephaly, neurologic and ocular disorders, and hypopigmentation involving skin and hair. This novel entity, known as oculocerebral hypopigmentation syndrome (OCHS) or Cross syndrome (OMIM 257800), is assumed to be autosomal recessive. However, its genetic cause is still unknown. Case Report: A 4-year-old girl is reported with OCHS, a history of recurrent infections and vertebral fusion of L4-L5. Central nervous system and cardiac imaging as well as metabolic screening were normal. Microscopic hair investigations did not show any melanin deposit defects. Results: Using molecular cytogenetics, we detected a de novo interstitial del(3)(q27.1q29) of the paternal chromosome. To our knowledge, this is the first molecular genetics finding in a patient with OCHS. Here we discuss the genotype-phenotype correlations and suggest candidate genes for this disorder. Conclusion: Investigating further patients would enable fine-mapping the OCHS locus and identifying its putative gene. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Mutations in the UPF3B gene, which encodes a protein involved in nonsense-mediated mRNA decay, have recently been described in four families with specific (Lujan–Fryns and FG syndromes), nonspecific X-linked mental retardation (XLMR) and autism. To further elucidate the contribution of UPF3B to mental retardation (MR), we screened its coding sequence in 397 families collected by the EuroMRX consortium. We identified one nonsense mutation, c.1081C>T/p.Arg361*, in a family with nonspecific MR (MRX62) and two amino-acid substitutions in two other, unrelated families with MR and/or autism (c.1136G>A/p.Arg379His and c.1103G>A/p.Arg368Gln). Functional studies using lymphoblastoid cell lines from affected patients revealed that c.1081C>T mutation resulted in UPF3B mRNA degradation and consequent absence of the UPF3B protein. We also studied the subcellular localization of the wild-type and mutated UPF3B proteins in mouse primary hippocampal neurons. We did not detect any obvious difference in the localization between the wild-type UPF3B and the proteins carrying the two missense changes identified. However, we show that UPF3B is widely expressed in neurons and also presents in dendritic spines, which are essential structures for proper neurotransmission and thus learning and memory processes. Our results demonstrate that in addition to Lujan–Fryns and FG syndromes, UPF3B protein truncation mutations can cause also nonspecific XLMR. We also identify comorbidity of MR and autism in another family with UPF3B mutation. The neuronal localization pattern of the UPF3B protein and its function in mRNA surveillance suggests a potential function in the regulation of the expression and degradation of various mRNAs present at the synapse. [ABSTRACT FROM AUTHOR]

Crepel A, Breckpot J, Fryns J-P, De la Marche W, Steyaert J, Devriendt K, Peeters H. DISC1 duplication in two brothers with autism and mild mental retardation. We describe the identification and delineation of an inherited 2.07 Mb microduplication in 1q42.2 in two brothers with autism and mild mental retardation. Since this duplication was not present in 1577 Belgian persons, we consider this as an extremely rare variant which has the potential to provide further insight into the genetics of autism. The duplication contains seven genes including the DISC1 gene, an interesting candidate gene that has been associated to schizophrenia, bipolar disorder, autism and Asperger syndrome. In this report we describe additional analyses undertaken to investigate the causal relationship of the duplication to the autism phenotype. We conclude that the 1q42.2 microduplication probably confers susceptibility to autism in the current family. This study is a typical illustration of the difficult interpretation of causality of a very rare variant in neuropsychiatric disease and the challenge of genetic counselling in a particular family. [ABSTRACT FROM AUTHOR]

Focal dermal hypoplasia (FDH), Goltz or Goltz–Gorlin syndrome, is an X-linked dominant multisystem disorder characterized primarily by involvement of the skin, skeletal system and eyes. We screened for mutations in the PORCN gene in eight patients of Belgian and Finnish origin with firm clinical suspicion of FDH. First, we performed quantitative PCR (qPCR) analysis to define the copy number at this locus. Next, we sequenced the coding regions and flanking intronic sequences of the PORCN gene. Three de novo mutations were identified in our patients with FDH: a 150-kb deletion removing six genes including PORCN, as defined by qPCR and X-array-CGH, and two heterozygous missense mutations; c.992T>G (p.L331R) in exon 11 and c.1094G>A (p.R365Q) in exon 13 of the gene. Both point mutations changed highly conserved amino acids and were not found in 300 control X chromosomes. The three patients in whom mutations were identified all present with characteristic dermal findings together with limb manifestations, which were not seen in our mutation-negative patients. The clinical characteristics of our patients with PORCN mutations were compared with the previously reported mutation-positive cases. In this report, we summarize the literature on PORCN mutations and associated phenotypes. [ABSTRACT FROM AUTHOR]

Cohen syndrome is an autosomal recessive disorder that is characterized by mental retardation, facial dysmorphism, microcephaly, retinal dystrophy, truncal obesity, joint laxity and intermittent neutropenia. Mutations in the VPS13B (COH1) gene underlie Cohen syndrome. In approximately 70% of the patients mutations in the gene are identified on both alleles, while in about 30% only a mutation in a single allele or no mutant allele is detected. The VPS13B locus was recently added to the growing list of benign copy number variants. We hypothesized that patients with unexplained Cohen syndrome would harbour deletions affecting the VPS13B locus. We screened 35 patients from 26 families with targeted array CGH and identified 7 copy number alterations: 2 homozygous and 5 heterozygous deletions. Our results show that deletions are an important cause of Cohen syndrome and screening for copy number alterations of VPS13B should be an integral part of the diagnostic work-up of these patients. These findings have important consequences for the diagnosis of patients with genetic disorders in general since, as we highlight, rare benign copy number variants can underly autosomal recessive disorders and lead to disease in homozygous state or in compound heterozygosity with another mutation. © 2009 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Background: Genomic disorders are often caused by non-allelic homologous recombination between segmental duplications. Chromosome 16 is especially rich in a chromosome-specific low copy repeat, termed LCR16. Methods and Results: A bacterial artificial chromosome (BAC) array comparative genome hybridisation (CGH) screen of 1027 patients with mental retardation and/or multiple congenital anomalies (MR/MCA) was performed. The BAC array CGH screen identified five patients with deletions and five with apparently reciprocal duplications of 16p13 covering 1.65 Mb, including 15 RefSeq genes. In addition, three atypical rearrangements overlapping or flanking this region were found. Fine mapping by high-resolution oligonucleotide arrays suggests that these deletions and duplications result from non-allelic homologous recombination (NAHR) between distinct LCR16 subunits with >99% sequence identity. Deletions and duplications were either de novo or inherited from unaffected parents. To determine whether these imbalances are associated with the MR/MCA phenotype or whether they might be benign variants, a population of 2014 normal controls was screened. The absence of deletions in the control population showed that 16p13.11 deletions are significantly associated with MR/MCA (p = 0.0048). Despite phenotypic variability, common features were identified: three patients with deletions presented with MR, microcephaly and epilepsy (two of these had also short stature), and two other deletion carriers ascertained prenatally presented with cleft lip and midline defects. In contrast to its previous association with autism, the duplication seems to be a common variant in the population (5/1682, 0.29%). Conclusion: These findings indicate that deletions inherited from clinically normal parents are likely to be causal for the patients' phenotype whereas the role of duplications (de novo or inherited) in the phenotype remains uncertain. This difference in knowledge regarding the clinical relevance of the deletion and the duplication causes a paradigm shift in (cyto)genetic counselling. [ABSTRACT FROM AUTHOR]

The article reports on the facial dysmorphy in the newly recognized microdeletion 2p 15-p16.1 refined to a 570 kb region in 2p15. It is stated that Rajcan-Separovic characterized a new microdeletion syndrome involving chromosome 2p15-16.1 in two patients with an autistic disorder and multiple congenital anomalities with recognizable dysmorphic features. It is said that a 570 kb de novo microdeletion at 2p15 was detected.

Background: Immunodeficiency, centromeric instability and facial dysmorphism (ICF syndrome) is a rare autosomal recessive disease characterised by facial dysmorphism, immunoglobulin deficiency and branching of chromosomes 1 9 and 16 after PHA stimulation of lymphocytes. Hypomethylation of DNA of a small fraction of the genome is an unusual feature of ICF patients which is explained by mutations in the DNA methyltransferase gene DNMT3B in some, but not all, ICE patients. Objective: To obtain a comprehensive description of the clinical features of this syndrome as well as genotype- phenotype correlations in ICF patients. Methods: Data on ICF patients were obtained by literature search and additional information by means of questionnaires to corresponding authors. Results and conclusions: 45 patients all with proven centromeric instability were included in this study. Facial dysmorphism was found to be a common characteristic (n = 41/42), especially epicanthic folds, hypertelorism, flat nasal bridge and low set ears. Hypo- or agamma-globulinaemia was demonstrated in nearly all patients (n = 39/44). Opportunistic infections were seen in several patients, pointing to a T cell dysfunction. Haematological malignancy was documented in two patients. Life expectancy of ICE patients is poor, especially those with severe infections in infancy or chronic gastrointestinal problems and failure to thrive. Early diagnosis of ICF is important since early introduction of immunoglobulin supplementation can improve the course of the disease. Allogeneic stem cell transplantation should be considered as a therapeutic option in patients with severe infections or failure to thrive. Only 19 of 34 patients showed mutations in ONMT3B, suggesting genetic heterogeneity. No genotype-phenotype correlation was found between patients with and without ONMT3B mutations. [ABSTRACT FROM AUTHOR]

Aim and method: We analysed DNA samples isolated from individuals born with cleft lip and cleft palate to identify deletions and duplications of candidate gene loci using array comparative genomic hybridisation (array-CGH). Results: Of 83 syndromic cases analysed we identified one subject with a previously unknown 2.7 Mb deletion at 22q11.21 coinciding with the DiGeorge syndrome region. Eighteen of the syndromic cases had clinical features of Van der Woude syndrome and deletions were identified in five of these, all of which encompassed the interferon regulatory factor 6 (IRF6) gene. In a series of 104 non-syndromic cases we found one subject with a 3.2 Mb deletion at chromosome 6q25.1-25.2 and another with a 2.2 Mb deletion at 10q26.11-26.13. Analyses of parental DNA demonstrated that the two deletion cases at 22q11.21 and 6q25.1-25.2 were de novo, while the deletion of 10q26.11-26.13 was inherited from the mother, who also has a cleft lip. These deletions appear likely to be causally associated with the phenotypes of the subjects. Estrogen receptor 1 (ESR1) and fibroblast growth factor receptor 2 (FGFR2) genes from the 6q25.1-25.2 and 10q26.11-26.13, respectively, were identified as likely causative genes using a gene prioritisation software. Conclusion: We have shown that array-CGH analysis of DNA samples derived from cleft lip and palate subjects is an efficient and productive method for identifying candidate chromosomal loci and genes, complementing traditional genetic mapping strategies. [ABSTRACT FROM AUTHOR]

BACKGROUND: Prader-Willi syndrome (PWS) is a rare disorder caused by genetic defects in certain regions of chromosome 15q11-13. It is characterized by severe neonatal hypotonia and feeding problems, childhood-onset hyperphagia and obesity, short stature, facial dysmorphy, hypogonadism, learning and behavioural difficulties, and dental abnormalities. AIM: To describe the oro-dental phenotypic spectrum of patients with PWS. DESIGN: Fifteen PWS patients (3-35 years of age) being followed at the Centre for Human Genetics of the University Hospital of Leuven were examined at the dental clinic of the same institution. Medical information collected included age at diagnosis, body mass index (BMI) and level of cognitive functioning. Oral, clinical and radiological evaluations were performed. Caries experience (cavitation level), dental erosion and salivary flow rates were assessed. RESULTS: The 15 patients had dmft/DMFT scores ranging from 0 to 28, while nine were cavity-free. Those with severe caries experience also presented advanced dental erosion. BMI ranged from 16 to 42.6. There was no association between BMI and caries experience or erosive tooth wear. The PWS patients in our survey presented with a more favourable oral health status than those in previous studies. This might be due to early diet management or better oral hygiene during childhood or both. [ABSTRACT FROM AUTHOR]

BACKGROUND: Learning disabilities are one of the most consistently reported features in Velo-Cardio-Facial Syndrome (VCFS). Earlier reports on IQ in children with VCFS were, however, limited by small sample sizes and ascertainment biases. The aim of the present study was therefore to replicate these earlier findings and to investigate intellectual abilities in a large sample of children with VCFS. In addition, we aimed to identify factors that may contribute to within-syndrome variability in cognitive performance, such as the mode of inheritance of the deletion, sex, the presence of a heart defect and psychiatric morbidity. METHOD: IQ data of 103 children with VCFS (56 males, 47 females) were collected. Psychiatric diagnosis was additionally recorded. RESULTS: Children with VCFS had a mean full-scale IQ (FSIQ) of 73.48 (range: 50-109). There were no effects of sex, presence of a heart defect and psychiatric condition on intellectual profile. Inheritance of the deletion affected cognitive performance in VCFS, with children with familial deletions having significant lower FSIQ than children with a de novo deletion. CONCLUSIONS: Learning disabilities are very common in children with VCFS, although marked within syndrome variability is noted. One factor contributing to this variability seems to be the mode of inheritance of the deletion. [ABSTRACT FROM AUTHOR]

Background Learning disabilities are one of the most consistently reported features in Velo–Cardio–Facial Syndrome (VCFS). Earlier reports on IQ in children with VCFS were, however, limited by small sample sizes and ascertainment biases. The aim of the present study was therefore to replicate these earlier findings and to investigate intellectual abilities in a large sample of children with VCFS. In addition, we aimed to identify factors that may contribute to within-syndrome variability in cognitive performance, such as the mode of inheritance of the deletion, sex, the presence of a heart defect and psychiatric morbidity. Method IQ data of 103 children with VCFS (56 males, 47 females) were collected. Psychiatric diagnosis was additionally recorded. Results Children with VCFS had a mean full-scale IQ (FSIQ) of 73.48 (range: 50–109). There were no effects of sex, presence of a heart defect and psychiatric condition on intellectual profile. Inheritance of the deletion affected cognitive performance in VCFS, with children with familial deletions having significant lower FSIQ than children with a de novo deletion. Conclusions Learning disabilities are very common in children with VCFS, although marked within syndrome variability is noted. One factor contributing to this variability seems to be the mode of inheritance of the deletion. [ABSTRACT FROM AUTHOR]

Molecular karyotyping has revealed that microdeletions/duplications in the human genome are a major cause of multiple congenital anomalies associated with mental retardation (MCA/MR). The identification of a de novo chromosomal imbalance in a patient with MCA/MR is usually considered causal for the phenotype while a chromosomal imbalance inherited from a phenotypically normal parent is considered as a benign variation and not related to the disorder. Around 40% of imbalances in patients with MCA/MR in this series is inherited from a healthy parent and the majority of these appear to be (extremely) rare variants. As some of these contain known disease-causing genes and have also been found to be de novo in MCA/MR patients, this challenges the general view that such familial variants are innocent and of no major phenotypic consequence. Rather, we argue, that human genomes can be tolerant of genomic copy number variations depending on the genetic and environmental background and that different mechanisms play a role in determining whether these chromosomal imbalances manifest themselves. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Constitutional Complex Chromosomal Rearrangements (CCRs) are very rare. While the vast majority of CCRs involve more than one chromosome, only seven cases describe CCRs with four or more breakpoints within a single chromosome. Here, we present a patient with multiple congenital anomalies and mental retardation. Array Comparative Genomic Hybridisation (array CGH), FISH and Multicolour Banding FISH revealed a de novo complex rearrangement with two deletions, a duplication and an inversion of 4q. This CCR involving at least seven breakpoints is one of the most complex rearrangements of a single chromosome reported thus far. Potential mechanisms generating such complex rearrangements are discussed. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Chromosomal abnormalities are a major cause of mental retardation and multiple congenital anomalies (MCA/MR). Screening for these chromosomal imbalances has mainly been done by standard karyotyping. Previous array CGH studies on selected patients with chromosomal phenotypes and normal karyotypes suggested an incidence of 10–15% of previously unnoticed de novo chromosomal imbalances. Objective: To report array CGH screening of a series of 140 patients (the largest published so far) with idiopathic MCA/MR but normal karyotype. Results: Submicroscopic chromosomal imbalances were detected in 28 of the 140 patients (20%) and included 18 deletions, seven duplications, and three unbalanced translocations. Seventeen of 24 imbalances were confirmed de novo and 19 were assumed to be causal. Excluding subtelomeric imbalances, our study identified 11 clinically relevant interstitial submicroscopic imbalances (8%). Taking this and previously reported studies into consideration, array CGH screening with a resolution of at least 1 Mb has been undertaken on 432 patients with MCA/MR. Most imbalances are non-recurrent and spread across the genome. In at least 8.8% of these patients (38 of 432) de novo intrachromosomal alterations have been identified. Conclusions: Array CGH should be considered an essential aspect of the genetic analysis of patients with MCA/MR. In addition, in the present study three patients were mosaic for a structural chromosome rearrangement. One of these patients had monosomy 7 in as few as 8% of the cells, showing that array CGH allows detection of low grade mosaicisims. [ABSTRACT FROM AUTHOR]

Several studies have shown that array based comparative genomic hybridisation (CGH) is a powerful tool for the detection of copy number changes in the genome of individuals with a congenital disorder. In this study, 40 patients with non-specific X linked mental retardation were analysed with full coverage, X chromosomal, bacterial artificial chromosome arrays. Copy number changes were validated by multiplex ligation dependent probe amplification as a fast method to detect duplications and deletions in patient and control DNA. This approach has the capacity to detect copy number changes as small as 100 kb. We identified three causative duplications: one family with a 7 Mb duplication in Xp22.2 and two families with a 500 kb duplication in Xq28 encompassing the MECP2 gene. In addition, we detected four regions with copy number changes that were frequently identified in our group of patients and therefore most likely represent genomic polymorphisms. These results confirm the power of array CGH as a diagnostic tool, but also emphasise the necessity to perform proper validation experiments by an independent technique. [ABSTRACT FROM AUTHOR]

Mutations in the human ARX gene have been shown to cause nonsyndromic X-linked mental retardation (MRX) as well as syndromic forms such as X-linked lissencephaly with abnormal genitalia (XLAG), Partington syndrome and X-linked infantile spasm. The most common causative mutation, a duplication of 24 bp, was found in families with a variety of phenotypes, but not in the more severe XLAG phenotypes. The aim of the study was to access the frequency of ARX mutations in families with established or putative X-linked mental retardation (XLMR) collected by the European XLMR Consortium. We screened the entire coding region of ARX for mutations in 197 novel XLMR families by denaturing high-performance liquid chromatography, and we identified eight mutations (six c.428_451dup24, one insertion and one novel missense mutation p.P38S). To better define the prevalence of ARX mutations, we included previously reported results of 157 XLMR families. Together, these data showed the relatively high rate (9.5%) of ARX mutations in X-linked MR families and an expectedly low rate in families with affected brother pairs (2.2%). This study confirms that the frequency of ARX mutations is high in XLMR, and the analysis of ARX in MRX should not be limited to duplication. [ABSTRACT FROM AUTHOR]

Truncating mutations were found in the PHF8 gene (encoding the PHD finger protein 8) in two unrelated families with X linked mental retardation (XLMR) associated with cleft lip/palate (MIM 300263). Expression studies showed that this gene is ubiquitously transcribed, with strong expression of the mouse orthologue Phf8 in embryonic and adult brain structures. The coded PHF8 protein harbours two functional domains, a PHD finger and a JmjC (Jumonji-like C terminus) domain, implicating it in transcriptional regulation and chromatin remodelling. The association of XLMR and cleft lip/palate in these patients with mutations in PHF8 suggests an important function of PHF8 in midline formation and in the development of cognitive abilities, and links this gene to XLMR associated with cleft lip/palate. Further studies will explore the specific mechanisms whereby PHF8 alterations lead to mental retardation and midline defects. [ABSTRACT FROM AUTHOR]

Background: A new syndrome has been recognised following thorough analysis of patients with a terminal submicroscopic subtelomeric deletion of chromosome 9q. These have in common severe mental retardation, hypotonia, brachycephaly, flat face with hypertelorism, synophrys, anteverted nares, thickened lower lip, carp mouth with macroglossia, and conotruncal heart defects. The minimum critical region responsible for this 9q subtelomeric deletion syndrome (9q-) is approximately 1.2 Mb and encompasses at least 14 genes. Objective: To characterise the breakpoints of a de novo balanced translocation t(X;9)(pl1.23;q34.3) in a mentally retarded female patient with clinical features similar to the 9q- syndrome. Results: Sequence analysis of the break points showed that the translocation was fully balanced and only one gene on chromosome 9 was disrupted-Euchromatin Histone Methyl Transferasel (Eu-HMTase1)- encoding a histone H3 lysine 9 methyltransferase (H3-K9 HMTase). This indicates that haploinsufficiency of Eu-HMTase1 is responsible for the 9q submicroscopic subtelomeric deletion syndrome. This observation was further supported by the spatio-temporal expression of the gene. Using tissue in situ hybridisation studies in mouse embryos and adult brain, Eu-HMTasel was shown to be expressed in the developing nervous system and in specific peripheral tissues. While expression is selectively downregulated in adult brain, substantial expression is retained in the olfactory bulb, anterior/ventral lateral ventricular wall, and hippocampus and weakly in the piriform cortex. Conclusions: The expression pattern of this gene suggests a role in the CNS development and function, which is in line with the severe mental retardation and behaviour problems in patients who lack one copy of the gene. [ABSTRACT FROM AUTHOR]

In the present study the neuropsychological, academic and social-emotional profiles were examined in Neurofibromatosis type 1 (NF1) children17 NF1 children (ages 7–11) with NF1 without serious medical problems and with a full scale IQ (FSIQ) above 70.Wechsler Intelligence Scale for Children-Revised (WISC-R), academic tests and an exhaustive neuropsychological test battery were administered in all children. Parents and teachers filled out the Child Behavioural Checklist (CBCL) and Teacher Report Form (TRF), respectively, the NF1 children the Experienced Competence Scale for Children (ECSC).Nearly 50% (8/17) of the children showed learning disabilities, when corrected for IQ in the academic evaluations. Isolated impaired literacy skills, particularly spelling problems, were most frequent (4/8), whereas a pure arithmetic learning disability was rare (1/8). Three children presented both learning disabilities. Results on academic and neuropsychological tests did not fit the well-known types of learning disabilities– nonverbal learning disability (NLD) and dyslexia. Nearly all NF1 children showed visual perceptual and executive dysfunctions. In this study, teachers more frequently reported behavioural problems in NF1 children than parents, as opposed to literature data in a general population. The correspondence of the perception of internalizing problems between the children and teachers was greater than between children and their parents. No correlation was found between the performances on the WISC-R, specific neuropsychological results, academic performances and behavioural problems. The Deficiency in Attention, Motor and Perception (DAMP) concept seems most appropriate in order to describe the neuropsychological deficits and their repercussions on behavioural and academic performances seen in NF1 children. [ABSTRACT FROM AUTHOR]

Presents several clinical cases of patients with Wolf-Hirschhorn syndrome, a multiple malformation syndrome with distinct abnormal craniofacial features. Observation of 4p terminal deletions in patients; Use of micro-array comparative genomic hybridization to determine the size of the deletion of patients; Investigation of the patients; Conduct of DNA polymorphism studies to identify the origin of the deletions.

We review the different strategies currently used to try to identify susceptibility genes for idiopathic autism. Although identification of genes is usually straightforward in Mendelian disorders, it has proved to be much more difficult to establish in polygenic disorders like autism. Neither genome screens of affected siblings nor the large number of association studies using candidate genes have resulted in finding autism susceptibility genes. We focus on the alternative approach of 'positional cloning' through chromosomal aberrations in individuals with autism. In particular, balanced aberrations such as reciprocal translocations or inversions offer a unique opportunity, since only the genes in the breakpoint regions are candidate genes. This approach, in combination with others, is likely to produce results in the coming years. [ABSTRACT FROM AUTHOR]

Examines the zinc finger 81 (ZNF81) gene mutations associated with x-linked mental retardation. Absence of th full-length ZNF81 transcript in the patient cell line; Identification of the X chromosome breakpoint by Southern hybridization; Representation of a novel MRX gene which is causally involved in a minority of patients with non-specific X-linked mental retardation.

While current sequencing efforts consider the detection of alpha satellite repeats as logical end points for map construction, detailed maps of most pericentromeric regions are lacking to confirm this hypothesis. Here we identify the different alpha satellite families present at the pericentromeric region of chromosome 12. The order, size and location of these repeats is established using radiation hybrid analysis, pulsed field gel analysis and FISH and the maps are integrated with current sequence information. For the different classes of alpha satellites present at the chromosome 12 centromere the paralogs in the human genome were mapped by FISH. Unique sequences flanking the alpha satellite repeats were identified, some of which are not represented in the current draft sequence. This mapping effort localises the different alpha satellite repeats within the pericentromeric region and anchors them in the current maps. The novel sequences identified may serve as the end point for the ongoing sequencing efforts. Copyright © 2003 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Describes a molecular genetic analysis of a male with autism, with a de novo balanced translocation t(5;13)(q12.1;q13.2). Case of boy of healthy, unrelated parents; Determination of breakpoints on the chromosomes using molecular analysis; Disruption of the neurobeachin encoding gene; Role of neurobeachin during brain development.

Heterotaxia is an aetiologically heterogeneous condition caused by an abnormal left-right axis formation, resulting in reversed left-right polarity of one or more organ systems. In a patient with heterotaxia and a de novo reciprocal translocation t(6;18)(q21;q21), we found that the PA26 gene was disrupted by the 6q21 breakpoint. Northern blot analysis showed decreased expression of the PA26 gene in an Epstein-Barr virus-transformed cell line of this patient. During early embryogenesis of Xenopus, the orthologue of PA26, XPA26 is exclusively expressed in the notochord, a midline structure. This further supports a possible role of PA26 in human situs determination. Mutation analysis of human PA26 gene in 40 unrelated individuals with unexplained heterotaxia failed to identify mutations, indicating that PA26 mutations are not a frequent cause of heterotaxia in humans. Analysis of the PA26 gene structure resulted in the identification of a novel PA26-related gene family, which we have named the sestrin family, and which comprises three closely related genes in human and in mouse. [ABSTRACT FROM AUTHOR]

The gene encoding fatty acid CoA ligase 4 (FACL4) is mutated in families with non-specific X linked mental retardation (MRX) and is responsible for cognitive impairment in the contiguous gene syndrome ATS-MR (Alport syndrome and mental retardation), mapped to Xq22.3. This finding makes this gene a good candidate for other mental retardation disorders mapping in this region. We have found a missense mutation in MRX68. The mutation (c.1001C>T in the brain isoform) cosegregates with the disease and changes a highly conserved proline into a leucine (p.P375L) in the first luciferase domain, which markedly reduces the enzymatic activity. Furthermore, all heterazygous females showed completely skewed X inactivation in blood leucocytes, as happens in all reported females with other FACL4 point mutations or deletions. Since the FACL4 gene is highly expressed in brain, where it encodes a brain specific isoform, and is located in hippocampal and cerebellar neurones, a role for this gene in cognitive processes can be expected. Here we report the third MRX family with a FACL4 mutation and describe the development of a rapid enzymatic assay on peripheral blood that we propose as a sensitive, robust, and efficient diagnostic tool in mentally retarded males. [ABSTRACT FROM AUTHOR]

This review covers the history and nosology of X-linked mental retardation (XLMR) in which the following, largely clinically based, subclassification was used: fragile X syndrome (FRAXA), syndromic forms (MRXS) and non-specific forms (MRX). After the discovery of the FMR2 gene at the FRAXE site, 10 MRX genes have been identified in the last 6 years. A short description is given of the strategies used to identify the genes that cause mental retardation (MR). Furthermore, their potential functions and the association with MR will be discussed. It is emphasized that mutations in several of these MR genes can result in non-specific, as well as in syndromic forms of XLMR. Present findings stress the importance of accurate clinical evaluation. Most considerably, genotype–phenotype correlation studies of affected individuals in XLMR families with MRX gene mutations are necessary to define the criteria of MRX vs MRXS subclassification. [ABSTRACT FROM AUTHOR]

Segmental duplications or low-copy repeats (LCRs) on chromosome 22q11 have been implicated in several chromosomal rearrangements. The presence of AT-rich regions in these duplications may lead to the formation of hairpin structures, which facilitate chromosomal rearrangement. Here we report the involvement of such a low-copy repeat in a t(X;22) associated with a neural tube defect. Molecular analysis of the chromosomal breakpoints revealed that the chromosome 22 breakpoint maps in the palindromic non-AT-rich NF1 -like region of low-copy repeat B (LCR-B). No palindromic region was encountered near the breakpoint on chromosome X. Our findings confirm that there is no single mechanism leading to translocations with chromosome 22q11 involvement. Because LCR-B does not contain genes involved in neural tube development, we believe that the gene responsible for the observed phenotype is most likely localized on chromosome X. [ABSTRACT FROM AUTHOR]

Presents a case of severe digital abnormalities in a patient heterozygous for both a novel missense mutation in HOXD13 and a polyalanine tract expansion in HOXA13. Key issues of interest; Analysis of pertinent topics and relevant issues; Implications on medical genetics.

Studies PTPN11 gene mutations in an autosomal dominant disorder combining multiple Lentigines, ECG abnormalities, ocular hypertelorism, pulmonary stenosis, abnormalities of the genitalia, retardation of growth and deafness. Key issues of interest; Analysis of pertinent topics and relevant issues; Theoretical significance to medical genetics.

Molecular analysis of the reciprocal chromosomal translocation t(12;22)(p11.2;q13.3) cosegregating with a complex type of synpolydactyly showed involvement of an alternatively spliced exon of the fibulin-1 gene (FBLN1 located in 22q13.3) and the C12orf2 (HoJ-1) gene on the short arm of chromosome 12. Investigation of the possible functional involvement of the fibulin-1 protein (FBLN1) in the observed phenotype showed that FBLN1 is expressed in the extracellular matrix (ECM) in association with the digits in the developing limb. Furthermore, fibroblasts derived from patients with the complex type of synpolydactyly displayed alterations in the level of FBLN1-D splice variant incorporated into the ECM and secreted into the conditioned culture medium. By contrast, the expression of the FBLN1-C splice variant was not perturbed in the patient fibroblasts. Based on these findings, we propose that the t(12;22) results in haploinsufficiency of the FBLN1-D variant, which could lead to the observed limb malformations. [ABSTRACT FROM AUTHOR]

Describes a family with autosomal dominant isolated velopharyngeal incompetence, a velopgharyngeal disorder. Manifestations of the disease; Hypernasal speech of the patients; Role of soft palate in the velopharyngeal insufficiency.

AbstractPrader–Willi syndrome (PWS) is a genetic disorder caused by the loss of the paternal contribution of the proximal part (15q11–q13) of the long arm of chromosome 15 (i.e. deletion, disomy and imprinting mutation). The syndrome is associated with distinct physical dysmorphism, as well as with specific behavioural and psychopathological characteristics. Psychiatric symptoms in adolescence and adulthood have been described, including acute cycloid psychosis, and obsessive compulsive, bipolar and pervasive developmental disorders. At the Centre for Human Genetics in Leuven, Belgium, 53 individuals (31 children and adolescents, and 22 adults) have been followed up for 15 years by a special multidisciplinary team. Attention was given to their medical, cognitive, behavioural and emotional development, and the evolution of psychiatric disorders in adolescence and adulthood. This study describes the psychiatric problems in four patients diagnosed with acute cycloid psychosis and traces their development from infancy to adolescence. Four other individuals needed psychiatric evaluation and treatment, and could be diagnosed as having unspecified bipolar disorder, also termed unstable mood disorder. Both groups were compared, and significant differences in early development and later evolution into adulthood were noted. The individuals with PWS who later developed psychotic episodes were described as active and extrovert toddlers, and showed autistic behaviour during their primary school education. Their intellectual functioning was in the moderate to severely retarded range. The individuals with PWS who later developed an unstable mood disorder were described as rather passive and introvert toddlers, and they presented less disturbed behaviour during their primary school education. The intellectual functioning of these subjects was in the normal to borderline range. [ABSTRACT FROM AUTHOR]

Presents a letter to the editor of the periodical "Journal of Medical Genetics," concerning interstitial deletion of chromosome 11 in a boy with mild developmental delay.

Presents a letter to the editor about pregnancy outcome and long term prognosis in children born after second trimester amniocentesis for maternal serum positive triple test screening and normal prenatal karyotype.

Synpolydactyly (SPD) is a rare malformation of the distal limbs known to be caused by mutations in HOXD13. We have previously described a complex form of SPD associated with synostoses in three members of a Belgian family, which co-segregates with a t(12;22)(p11.2;q13.3) chromosomal translocation. The chromosome 12 breakpoint of this translocation maps to 12p11.2 between markers D12S1034 and D12S1596. Here we show that a mutation in the HOXD13 gene is not responsible for the phenotype, and present a physical map of the region around the 12p11.2 breakpoint. Starting from D12S1034 and D12S1596, we have established a contig approximately 1.5 Mb in length, containing 13 YAC clones, 16 BAC clones, and 11 cosmid clones. FISH analysis shows that cosmid LL12NCO1-149H4 maps across the breakpoint, and Southern blot experiments using fragments of this cosmid as probes identify a rearranged BamHI fragment in the patients carrying the translocation. A search for expressed sequences within the contig have so far revealed one CpG island, seven anonymous ESTs and three previously characterised genes, DAD-R, KRAG and HT21, all of which were found not to be directly disrupted by the translocation. The gene represented by EST R72964 was found to be disrupted by the translocation. These findings lay the groundwork for further efforts to characterise a gene critical for normal distal limb development that is perturbed by this translocation. [ABSTRACT FROM AUTHOR]

Mental retardation is a very common and extremely heterogeneous disorder that affects about 3% of the human population. Its molecular basis is largely unknown, but many loci have been mapped to the X chromosome. We report on two mentally retarded females with X;autosome translocations and breakpoints in Xp11, viz., t(X;17)(p11;p13) and t(X;20)(p11;q13). (Fiber-) FISH analysis assigned the breakpoints to different subbands, Xp11.4 and Xp11.23, separated by approximately 8 Mb. High-resolution mapping of the X- chromosome breakpoints using Southern blot hybridization resulted in the isolation of breakpoint-spanning genomic subclones of 3 kb and 0.5 kb. The Xp11.4 breakpoint is contained within a single copy sequence, whereas the Xp11.23 breakpoint sequence resembles an L1 repetitive element. Several expressed sequences map close to the breakpoints, but none was found to be inactivated. Therefore, mechanisms other than disruption of X-chromosome genes likely cause the phenotypes. Copyright © 2000 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The occurrence of more than two small accessory chromosomes (SACs) in a single individual is extremely rare. Here, we characterize six SACs found in the cells of two different tissues of a moderately mentally retarded male. Microdissection combined with regular FISH demonstrates that the SACs are ring chromosomes derived from the centromeres of different chromosomes. The SACs are often associated with the centromeres of other chromosomes. Immunofluorescence with an anti-CENP-C antibody demonstrates that the SACs contain an active centromere. A possible mechanism by which the SACs originated and their clinical relevance are discussed. [ABSTRACT FROM AUTHOR]