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Objective: We sought to compare our 5-year program of fragile X screening of high-risk gravid women with our program of fragile X testing of affected individuals (probands).Study Design: All women referred to the prenatal genetics clinic from 1994 to 1998 who had a family history of unspecified mental retardation or learning or behavioral disorders (known fragile X families excluded) were offered fragile X screening. Results were compared with those of probands with the same diagnoses who underwent fragile X testing during the same time period.Results: We counseled 12,349 prenatal patients from 1994-1998, of whom 263 (2.1%) had a positive family history and underwent fragile X screening. No mutations or premutations were identified. In contrast, 31 (1.9%) of 1637 affected probands who underwent fragile X testing during the same time period had positive results, which was a significant difference (0/263 vs 31/1637; P <.05).Conclusions: Testing the affected proband is superior to screening the pregnant relative of the proband for identification of families at risk for fragile X syndrome. [ABSTRACT FROM AUTHOR]

INTRODUCTION: human immunodeficiency Virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV) are the three most common chronic viral infections worldwide, specifically in sub-Saharan Africa (SSA). This study aimed to determine the sero-epidemiology of HIV, HBV and HCV infections in a rural setting of the West region of Cameroon, a SSA country. METHODS: we conducted a cross-sectional study from August 2 to 5, 2014 in the three health districts of the Menoua Division, West region of Cameroon. Sixteen villages were randomly selected. Participants were currently living in the Division at the time of the survey and enrolled after they had provided a signed consent form. HIV screening used the "Determine test" followed by Hexagon HIV for positive cases to the first assay. HBV and HCV were detected using DIASpot HBsAg and DIASpot HCV-Ab, respectively. RESULTS: on the whole, 612 subjects consented to take part in this study, of whom 71.1% were females. Mean age of the study population was 45.3 ' 17.9 years. The seroprevalences of HIV, HBV and HCV infections were 1.0% (6/582), 4.5% (20/443) and 6.3% (23/365), respectively. The 41-50 years age group was the most represented among HIV-positive subjects. HBV prevalence was higher in the 21-30 years age group (13.4%), followed by the 51-60 years age group (7.8%), with a significant difference of prevalences among age groups (p = 0.002). All HCV-positive cases were above 40 years of age with a higher prevalence in the 70 years age group (33.3%) followed by the 61-70 years age group (14.5%); there was a significant difference between the age groups (p = 0.001). CONCLUSION: the seroprevalences of HIV, HBV, and HCV infections in the Menoua Division of the West region of Cameroon were 1.0%, 4.5% and 6.3%, respectively. Preventive measures against these health threats need to be reinforced in this setting.

Background: 22q11.2 microdeletion is the most common microdeletion syndrome in humans with a prevalence of 13 per 100 000 live births, and it is a multisystem condition with variable phenotypic presentations., Methods: We present a case of an adult patient with Dandy-Walker syndrome who presented to our epilepsy clinic with 2 years of new-onset seizures and cognitive decline and 1 year of psychotic symptoms., Results: Patient had a non-revealing autoimmune and malignancy work-up. Continuous scalp vEEG study showed bursts of 1-2 Hz generalized fronto-centrally predominant spike or polyspike and slow wave discharges. Several myoclonic jerks were time-locked with the generalized discharges indicative of cortical myoclonus. MRI brain revealed periventricular nodular heterotopia in addition to findings suggestive of Dandy-Walker syndrome. Array-based comparative genomic hybridization demonstrated a 22q11.2 microdeletion seen in 22q11.2 deletion syndrome., Conclusion: Our case illustrates the challenges of diagnosing genetic disorders in adults especially when the initial diagnosis is dependent on a number of factors, including the patient's age, the severity of the phenotypic features, and the awareness of the physician., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Tyler E. Gaston has received a consulting fee from GW Biosciences within the last 2 years. Mike Zhang has received personal compensation as a consultant to Neurelis in 2023. The remaining authors have no conflicts of interest., (© The Author(s) 2024.)

Tubulin, one of the most abundant cytoskeletal building blocks, has numerous isotypes in metazoans encoded by different conserved genes. Whether these distinct isotypes form cell type- and context-specific microtubule structures is poorly understood. Based on a cohort of 12 patients with primary ciliary dyskinesia as well as mouse mutants, we identified and characterized variants in the TUBB4B isotype that specifically perturbed centriole and cilium biogenesis. Distinct TUBB4B variants differentially affected microtubule dynamics and cilia formation in a dominant-negative manner. Structure-function studies revealed that different TUBB4B variants disrupted distinct tubulin interfaces, thereby enabling stratification of patients into three classes of ciliopathic diseases. These findings show that specific tubulin isotypes have distinct and nonredundant subcellular functions and establish a link between tubulinopathies and ciliopathies.

Neurodevelopmental disorders (NDDs) result from highly penetrant variation in hundreds of different genes, some of which have not yet been identified. Using the MatchMaker Exchange, we assembled a cohort of 27 individuals with rare, protein-altering variation in the transcriptional coregulator ZMYM3, located on the X chromosome. Most (n = 24) individuals were males, 17 of which have a maternally inherited variant; six individuals (4 male, 2 female) harbor de novo variants. Overlapping features included developmental delay, intellectual disability, behavioral abnormalities, and a specific facial gestalt in a subset of males. Variants in almost all individuals (n = 26) are missense, including six that recurrently affect two residues. Four unrelated probands were identified with inherited variation affecting Arg441, a site at which variation has been previously seen in NDD-affected siblings, and two individuals have de novo variation resulting in p.Arg1294Cys (c.3880C>T). All variants affect evolutionarily conserved sites, and most are predicted to damage protein structure or function. ZMYM3 is relatively intolerant to variation in the general population, is widely expressed across human tissues, and encodes a component of the KDM1A-RCOR1 chromatin-modifying complex. ChIP-seq experiments on one variant, p.Arg1274Trp, indicate dramatically reduced genomic occupancy, supporting a hypomorphic effect. While we are unable to perform statistical evaluations to definitively support a causative role for variation in ZMYM3, the totality of the evidence, including 27 affected individuals, recurrent variation at two codons, overlapping phenotypic features, protein-modeling data, evolutionary constraint, and experimentally confirmed functional effects strongly support ZMYM3 as an NDD-associated gene., Competing Interests: Declaration of interests J.L.B., Y.C., B.R.L., M.P.N., A.G.N., and H.Z.E. are employees of GeneDx, LLC. S.E.A. is a cofounder and CEO of MediGenome, the Swiss Institute of Genomic Medicine. All other authors declare no competing interests., (Copyright © 2022 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Background: A neurodevelopmental syndrome was recently reported in four patients with SOX4 heterozygous missense variants in the high-mobility-group (HMG) DNA-binding domain. The present study aimed to consolidate clinical and genetic knowledge of this syndrome., Methods: We newly identified 17 patients with SOX4 variants, predicted variant pathogenicity using in silico tests and in vitro functional assays and analysed the patients' phenotypes., Results: All variants were novel, distinct and heterozygous. Seven HMG-domain missense and five stop-gain variants were classified as pathogenic or likely pathogenic variant (L/PV) as they precluded SOX4 transcriptional activity in vitro. Five HMG-domain and non-HMG-domain missense variants were classified as of uncertain significance (VUS) due to negative results from functional tests. When known, inheritance was de novo or from a mosaic unaffected or non-mosaic affected parent for patients with L/PV, and from a non-mosaic asymptomatic or affected parent for patients with VUS. All patients had neurodevelopmental, neurological and dysmorphic features, and at least one cardiovascular, ophthalmological, musculoskeletal or other somatic anomaly. Patients with L/PV were overall more affected than patients with VUS. They resembled patients with other neurodevelopmental diseases, including the SOX11- related and Coffin-Siris (CSS) syndromes, but lacked the most specific features of CSS., Conclusion: These findings consolidate evidence of a fairly non-specific neurodevelopmental syndrome due to SOX4 haploinsufficiency in neurogenesis and multiple other developmental processes., Competing Interests: Competing interests: AC and MJT are employees of GeneDx, Inc. Other authors have no competing interests., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Sleep apnea is a common disorder that represents a global public health burden. KCNK3 encodes TASK-1, a K + channel implicated in the control of breathing, but its link with sleep apnea remains poorly understood. Here we describe a new developmental disorder with associated sleep apnea (developmental delay with sleep apnea, or DDSA) caused by rare de novo gain-of-function mutations in KCNK3. The mutations cluster around the 'X-gate', a gating motif that controls channel opening, and produce overactive channels that no longer respond to inhibition by G-protein-coupled receptor pathways. However, despite their defective X-gating, these mutant channels can still be inhibited by a range of known TASK channel inhibitors. These results not only highlight an important new role for TASK-1 K + channels and their link with sleep apnea but also identify possible therapeutic strategies., (© 2022. The Author(s).)

Introduction: Ornithine transcarbamylase (OTC) deficiency is the most common urea cycle disorder, inherited in an X-linked manner. Males are severely affected. Female phenotypes vary from asymptomatic to severe, and symptoms may be triggered by high metabolic states like childbirth. Literature on OTC deficiency in pregnancy and placental pathology is limited., Methods: Pathology records were searched at a single referral center from 2000-2020 and identified three placental cases from two mothers heterozygous for OTC deficiency. Placental pathology and maternal and neonatal history were reviewed in detail., Results: The placenta from one symptomatic mother carrying an affected male fetus showed widespread high-grade fetal vascular malperfusion (FVM) lesions of varying age. These lesions were not seen in the two placentas from the asymptomatic mother., Discussion: In cases of symptomatic maternal OTC deficiency, our findings highlight the need for placental examination. Since thrombotic events in the placenta have the potential to associate with fetal and neonatal endothelial damage, a high index of suspicion for neonatal thrombosis may be warranted.

Objective: Spondyloarthritis (SpA) and Takayasu arteritis (TA) are 2 chronic inflammatory diseases; their coexistence in a single patient is uncommon. The aims of our study were to describe clinical features of patients having SpA associated with TA and to identify some characteristics of the types of patients with SpA associated with TA. We also analyzed treatments used in this context., Methods: This French multicenter retrospective survey called for observations on behalf of the Club Rhumatismes et Inflammations, with a standardized questionnaire established by the investigators., Results: We included 14 patients (women: 10/14; median age at SpA diagnosis: 43.5 yrs, ranging from 19 to 63). Subtypes of SpA were ankylosing spondylitis (n = 11), psoriatic arthritis (n = 2), and synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome (n = 1). HLA-B27 was positive in 3 cases, negative in 9, and unknown in 2. SpA was diagnosed before TA in 13 cases. Imaging findings compatible with the diagnosis of TA were found with computed tomography (11/14) and/or Doppler ultrasound (10/14). Laboratory tests showed increased acute-phase reactants in all cases (C-reactive protein ≥ 25 mg/l in 71% of the cases). All patients except 1 received corticosteroids and 7 were treated with anti-tumor necrosis factor (anti-TNF)., Conclusion: Association of SpA and TA is rare but probably not coincidental. Peripheral pulse palpation and vascular auscultation should be systematic and are the first indicators of TA in patients with SpA. Moreover, increased acute-phase reactants during SpA followup should lead to search for TA. Finally, there are therapeutic implications because anti-TNF are efficient in SpA and might be efficient in TA.

Background: Elevated urinary excretion of orotic acid is associated with treatable disorders of the urea cycle and pyrimidine metabolism. Establishing the correct and timely diagnosis in a patient with orotic aciduria is key to effective treatment. Uridine monophosphate synthase is involved in de novo pyrimidine synthesis. Uridine monophosphate synthase deficiency (or hereditary orotic aciduria), due to biallelic mutations in UMPS, is a rare condition presenting with megaloblastic anemia in the first months of life. If not treated with the pyrimidine precursor uridine, neutropenia, failure to thrive, growth retardation, developmental delay, and intellectual disability may ensue., Methods and Results: We identified mild and isolated orotic aciduria in 11 unrelated individuals with diverse clinical signs and symptoms, the most common denominator being intellectual disability/developmental delay. Of note, none had blood count abnormalities, relevant hyperammonemia or altered plasma amino acid profile. All individuals were found to have heterozygous alterations in UMPS. Four of these variants were predicted to be null alleles with complete loss of function. The remaining variants were missense changes and predicted to be damaging to the normal encoded protein. Interestingly, family screening revealed heterozygous UMPS variants in combination with mild orotic aciduria in 19 clinically asymptomatic family members., Conclusions: We therefore conclude that heterozygous UMPS-mutations can lead to mild and isolated orotic aciduria without clinical consequence. Partial UMPS-deficiency should be included in the differential diagnosis of mild orotic aciduria. The discovery of heterozygotes manifesting clinical symptoms such as hypotonia and developmental delay are likely due to ascertainment bias.

Purpose: The 2010 consensus statement on diagnostic chromosomal microarray (CMA) testing recommended an array resolution ≥400 kb throughout the genome as a balance of analytical and clinical sensitivity. In spite of the clear evidence for pathogenicity of large copy-number variants (CNVs) in neurodevelopmental disorders and/or congenital anomalies, the significance of small, nonrecurrent CNVs (<500 kb) has not been well established in a clinical setting., Methods: We investigated the clinical significance of all nonpolymorphic small, nonrecurrent CNVs (<500 kb) in patients referred for CMA clinical testing over a period of 6 years, from 2009 to 2014 (a total of 4,417 patients). We excluded from our study patients with benign or likely benign CNVs and patients with only recurrent microdeletions/microduplications <500 kb., Results: In total, 383 patients (8.67%) were found to carry at least one small, nonrecurrent CNV, of whom 176 patients (3.98%) had one small CNV classified as a variant of uncertain significance (VUS), 45 (1.02%) had two or more small VUS CNVs, 20 (0.45%) had one small VUS CNV and a recurrent CNV, 113 (2.56%) had one small pathogenic or likely pathogenic CNV, 17 (0.38%) had two or more small pathogenic or likely pathogenic CNVs, and 12 (0.27%) had one small pathogenic or likely pathogenic CNV and a recurrent CNV. Within the pathogenic group, 80 of 142 patients (56% of all small pathogenic CNV cases) were found to have a single whole-gene or exonic deletion. The themes that emerged from our study are presented in the Discussion section., Conclusions: Our study demonstrates the diagnostic clinical relevance of small, nonrecurrent CNVs <500 kb during CMA clinical testing and underscores the need for careful clinical interpretation of these CNVs.Genet Med 19 4, 377-385.

Uniparental disomy (UPD) for imprinted chromosomes can cause abnormal phenotypes due to absent or overexpression of imprinted genes. UPD(14)pat causes a unique constellation of features including thoracic skeletal anomalies, polyhydramnios, placentomegaly, and limited survival; its hypothesized cause is overexpression of paternally expressed RTL1, due to absent regulatory effects of maternally expressed RTL1as. UPD(14)mat causes a milder condition with hypotonia, growth failure, and precocious puberty; its hypothesized cause is absence of paternally expressed DLK1. To more clearly establish how gains and losses of imprinted genes can cause disease, we report six individuals with copy number variations of the imprinted 14q32 region identified through clinical microarray-based comparative genomic hybridization. Three individuals presented with UPD(14)mat-like phenotypes (Temple syndrome) and had apparently de novo deletions spanning the imprinted region, including DLK1. One of these deletions was shown to be on the paternal chromosome. Two individuals with UPD(14)pat-like phenotypes had 122-154kb deletions on their maternal chromosomes that included RTL1as but not the differentially methylated regions that regulate imprinted gene expression, providing further support for RTL1 overexpression as a cause for the UPD(14)pat phenotype. The sixth individual is tetrasomic for a 1.7Mb segment, including the imprinted region, and presents with intellectual disability and seizures but lacks significant phenotypic overlap with either UPD(14) syndrome. Therefore, the 14q32 imprinted region is dosage sensitive, with deletions of different critical regions causing UPD(14)mat- and UPD(14)pat-like phenotypes, while copy gains are likely insufficient to recapitulate these phenotypes.

Context: Mineralocorticoid receptors (MRs) contribute to the negative feedback of the hypothalamic-pituitary-adrenal (HPA) axis in rodents. Studies with MR antagonists suggest a similar role in humans., Objective: The objective of the study was to establish whether loss-of-function mutations in NR3C2, encoding MR, cause activation of the HPA axis., Design and Setting: This was a case-control study in members of pedigrees from the PHA1.NET cohort, comprising patients with pseudohypoaldosteronism type 1 (PHA1) who are heterozygous for loss-of-function mutations in NR3C2 and healthy controls who are unaffected family members., Participants: Twelve adult patients with PHA1 (six men, six women) and 20 age-matched healthy controls (seven men, 13 women) participated in the study., Results: Patients with PHA1 had higher morning plasma cortisol (816 ± 85 vs 586 ± 50 nmol/L, P = .02) and increased 24-hour urinary excretion of cortisol metabolites (985 ± 150 vs 640 ± 46 μg/mmol creatinine, P = .03), independently of gender. After adjustment for gender, age, PHA1 diagnosis, and percentage body fat, higher plasma cortisol was associated with higher plasma renin, lower serum high-density lipoprotein-cholesterol, and higher waist circumference but not with blood pressure, carotid intima-media thickness, or echocardiographic parameters., Conclusions: Haploinsufficiency of MR in PHA1 causes HPA axis activation, providing genetic evidence that MR contributes to negative feedback in the human HPA axis. With limited sample size, initial indications suggest the resulting hypercortisolemia is related to the severity of MR deficiency and has adverse effects mediated by glucocorticoid receptors on liver lipid metabolism and adipose tissue distribution but does not adversely affect cardiac and vascular remodeling in the absence of normal signaling through the MR.

Mucopolysaccharidosis (MPS) II, or Hunter syndrome, is a lysosomal storage disease characterized by multi-systemic involvement and a progressive clinical course. Enzyme replacement therapy with idursulfase has been approved in more than 50 countries worldwide; however, safety and efficacy data from clinical studies are currently only available for patients 1.4 years of age and older. Sibling case studies of infants with MPS I, II, and VI who initiated ERT in the first weeks or months of life have reported no new safety concerns and a more favorable clinical course for the sibling treated in infancy than for the later-treated sibling. Here we describe our experiences with a case series of eight MPS II patients for whom idursulfase treatment was initiated at under 1 year of age. The majority of the patients were diagnosed because of a family history of disease. All of the infants displayed abnormalities consistent with MPS II at diagnosis. The youngest age at treatment start was 10 days and the oldest was 6.5 months, with duration of treatment varying between 6 weeks and 5.5 years. No new safety concerns were observed, and none of the patients experienced an infusion-related reaction. All of the patients treated for more than 6 weeks showed improvements and/or stabilization of some somatic manifestations while on treatment. In some cases, caregivers made comparisons with other affected family members and reported that the early-treated patients experienced a less severe clinical course, although a lack of medical records for many family members precluded a rigorous comparison.

In clinical diagnostics, both array comparative genomic hybridization (array CGH) and single nucleotide polymorphism (SNP) genotyping have proven to be powerful genomic technologies utilized for the evaluation of developmental delay, multiple congenital anomalies, and neuropsychiatric disorders. Differences in the ability to resolve genomic changes between these arrays may constitute an implementation challenge for clinicians: which platform (SNP vs array CGH) might best detect the underlying genetic cause for the disease in the patient? While only SNP arrays enable the detection of copy number neutral regions of absence of heterozygosity (AOH), they have limited ability to detect single-exon copy number variants (CNVs) due to the distribution of SNPs across the genome. To provide comprehensive clinical testing for both CNVs and copy-neutral AOH, we enhanced our custom-designed high-resolution oligonucleotide array that has exon-targeted coverage of 1860 genes with 60,000 SNP probes, referred to as Chromosomal Microarray Analysis - Comprehensive (CMA-COMP). Of the 3240 cases evaluated by this array, clinically significant CNVs were detected in 445 cases including 21 cases with exonic events. In addition, 162 cases (5.0%) showed at least one AOH region >10 Mb. We demonstrate that even though this array has a lower density of SNP probes than other commercially available SNP arrays, it reliably detected AOH events >10 Mb as well as exonic CNVs beyond the detection limitations of SNP genotyping. Thus, combining SNP probes and exon-targeted array CGH into one platform provides clinically useful genetic screening in an efficient manner.

SOX5 encodes a transcription factor involved in the regulation of chondrogenesis and the development of the nervous system. Despite its important developmental roles, SOX5 disruption has yet to be associated with human disease. We report one individual with a reciprocal translocation breakpoint within SOX5, eight individuals with intragenic SOX5 deletions (four are apparently de novo and one inherited from an affected parent), and seven individuals with larger 12p12 deletions encompassing SOX5. Common features in these subjects include prominent speech delay, intellectual disability, behavior abnormalities, and dysmorphic features. The phenotypic impact of the deletions may depend on the location of the deletion and, consequently, which of the three major SOX5 protein isoforms are affected. One intragenic deletion, involving only untranslated exons, was present in a more mildly affected subject, was inherited from a healthy parent and grandparent, and is similar to a deletion found in a control cohort. Therefore, some intragenic SOX5 deletions may have minimal phenotypic effect. Based on the location of the deletions in the subjects compared to the controls, the de novo nature of most of these deletions, and the phenotypic similarities among cases, SOX5 appears to be a dosage-sensitive, developmentally important gene., (© 2012 Wiley Periodicals, Inc.)

Monosomy 1p36 is a clinically recognizable syndrome that is considered to be the most common terminal deletion syndrome. It has characteristic clinical features that include craniofacial dysmorphism, congenital anomalies, hearing deficits, developmental delay, mental retardation, hypotonia, seizures, and brain anomalies. Brain anomalies in patients with 1p36 deletion are frequent but inconsistent. To date, 2 cases with monosomy 1p36 associated with periventricular nodular heterotopia (PNH) have been reported. We report a 2-month-old boy with multiple congenital anomalies; brain magnetic resonance imaging revealed PNH. The first 2 described cases were pure terminal deletions, whereas our patient carried unbalanced translocation due to an adjacent 1 segregation of a balanced maternal translocation, resulting in monosomy 1p36.3 and trisomy 19p13.3 identified by whole-genome array comparative genomic hybridization analysis. Our patient, with a smaller deletion that the 2 previously reported cases, can help narrow the critical region for PNH in association with the 1p36 deletion. Several potential candidate genes are discussed., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Rhizomelic chondrodysplasia punctata (RCDP) is an autosomal-recessive disorder resulting from mutations in one of three peroxisomal genes essential for ether lipid biosynthesis, PEX7 (RCDP1), GNPAT (RCDP2), and AGPS (RCDP3). Affected patients have characteristic features including shortening of the proximal long bones, epiphyseal stippling, bilateral cataracts, growth and developmental delays. Whereas the majority of patients have RCDP type 1, around 5% have RCDP type 2 or 3. We identified a patient with RCDP type 2 and an apparent homozygous deletion, c.1428delC, after full sequencing of his GNPAT genes. The father was heterozygous for this mutation, while sequencing of the maternal GNPAT genes revealed only wild-type sequence. Southern analyses performed on parental gDNA did not show evidence of a maternal gene deletion. Amplification and fragment analysis of dinucleotide repeat markers spanning chromosome 1 in the patient and both parents revealed paternal uniparental inheritance. We discuss the potential mechanisms causing uniparental disomy (UPD) in this patient and review the literature on chromosome 1 UPD. The absence of non-RCDP clinical features in this patient was consistent with previous literature supporting the absence of imprinted genes on chromosome 1. This first description of RCDP caused by UPD dramatically changes the parental recurrence risk, highlighting the value of obtaining parental genotypes when the proband has a putative homozygous mutation by sequence analysis., ((c) 2010 Wiley-Liss, Inc.)

Deoxyguanosine kinase (DGUOK) catalyzes the first step of the mitochondrial deoxypurine salvage pathway, the phosphorylation of purine deoxyribonucleosides. Mutations in the DGUOK gene have been linked to inherited mtDNA depletion syndromes, neonatal liver failure, nystagmus, and hypotonia. Previously, we reported the first case of a heterozygous unclassified c.592-4&#95;c.592-3delTT alteration in a patient with DGUOK deficiency without the demonstration of its pathogenicity (Dimmock et al., 2008). This alteration was predicted to cause aberrant splicing based upon two computer algorithms. We now report a homozygous c.592-4&#95;c.592-3delTT mutation found in two affected siblings of asymptomatic consanguineous parents. The proband presented with symptoms of idiopathic hepatitis, liver dysfunction, nystagmus, and retinal blindness. This individual died at 6months of age due to liver failure. This individual's affected sibling presented similarly and has remarkable elevations of tyrosine, methionine, and alanine. Many organic acids were elevated in urine, including lactic acid, Krebs cycle intermediates, and para-hydroxy compounds; ketone bodies were also present. RNA studies support aberrant splicing. Sequencing of cDNA detected exon 5 skipping in the two affected siblings, but not in the normal control. These results indicate that the homozygous c.592-4&#95;c.592-3delTT is deleterious and responsible for the DGUOK deficiency. The parents were subsequently confirmed to be carriers of this mutation. In summary, we have demonstrated that c.592-4&#95;c.592-3delTT is a pathogenic splice acceptor site mutation leading to DGUOK deficiency.

We report that eight heterozygous missense mutations in TUBB3, encoding the neuron-specific beta-tubulin isotype III, result in a spectrum of human nervous system disorders that we now call the TUBB3 syndromes. Each mutation causes the ocular motility disorder CFEOM3, whereas some also result in intellectual and behavioral impairments, facial paralysis, and/or later-onset axonal sensorimotor polyneuropathy. Neuroimaging reveals a spectrum of abnormalities including hypoplasia of oculomotor nerves and dysgenesis of the corpus callosum, anterior commissure, and corticospinal tracts. A knock-in disease mouse model reveals axon guidance defects without evidence of cortical cell migration abnormalities. We show that the disease-associated mutations can impair tubulin heterodimer formation in vitro, although folded mutant heterodimers can still polymerize into microtubules. Modeling each mutation in yeast tubulin demonstrates that all alter dynamic instability whereas a subset disrupts the interaction of microtubules with kinesin motors. These findings demonstrate that normal TUBB3 is required for axon guidance and maintenance in mammals.

Down syndrome (DS) is one of the most frequent congenital birth defects, and the most common genetic cause of mental retardation. In most cases, DS results from the presence of an extra copy of chromosome 21. DS has a complex phenotype, and a major goal of DS research is to identify genotype-phenotype correlations. Cases of partial trisomy 21 and other HSA21 rearrangements associated with DS features could identify genomic regions associated with specific phenotypes. We have developed a BAC array spanning HSA21q and used array comparative genome hybridization (aCGH) to enable high-resolution mapping of pathogenic partial aneuploidies and unbalanced translocations involving HSA21. We report the identification and mapping of 30 pathogenic chromosomal aberrations of HSA21 consisting of 19 partial trisomies and 11 partial monosomies for different segments of HSA21. The breakpoints have been mapped to within approximately 85 kb. The majority of the breakpoints (26 of 30) for the partial aneuploidies map within a 10-Mb region. Our data argue against a single DS critical region. We identify susceptibility regions for 25 phenotypes for DS and 27 regions for monosomy 21. However, most of these regions are still broad, and more cases are needed to narrow down the phenotypic maps to a reasonable number of candidate genomic elements per phenotype.

Purpose: To identify the genetic informational needs and assess the level of awareness about clinical genetic services among adults who use the internet., Methods: We created an online service called AsktheGeneticist (http://www.askthegen.org) to answer questions about medical genetics. Since 2003, we have received 4497 questions from every US state and 84 countries/territories. Genetic counselors draft answers to the questions submitted. The questions and answers are next reviewed by clinical geneticists, then organized by topic and uploaded to the site. A link to an online website-user satisfaction survey is e-mailed to the user with a link to their Q&A., Results: Before visiting AsktheGeneticist, 20% (50/247) of survey respondents were unaware that genetic services existed. After visiting our website, 23.5% (58) of survey respondents sought contact with a genetics health care professional, compared with <1% of patients who self-refer to a general genetics clinic (binomial test; P < 0.0001). Website users most often sought information about a known genetic condition in their family and the risk of recurrence., Conclusions: Our data suggest that the internet can be an effective tool for increasing the awareness of genetic services and identifying genetic informational needs of online adults, as well as for connecting patients with genetic services.

Chromosome 22 band q11.2 has been recognized to be highly susceptible to subtle microdeletions and microduplications, which have been attributed to the presence of several large segmental duplications; also known as low copy repeats (LCRs). These LCRs function as mediators of non-allelic homologous recombination (NAHR), which results in these chromosomal rearrangements as a result of unequal crossover. The four centromeric LCRs at proximal 22q11.2 have been previously implicated in recurrent chromosomal rearrangements including the DiGeorge/Velocardiofacial syndrome (DG/VCFs) microdeletion and its reciprocal microduplication. Recently, we and others have demonstrated that the four telomeric LCRs at distal 22q11.2 are causally implicated in a newly recognized recurrent distal 22q11.2 microdeletion syndrome in the region immediately telomeric to the DG/VCFs typically deleted region. Here we report on the clinical, cytogenetic, and array CGH studies of a 4.5-year-old girl with history of failure to thrive, developmental delay (DD), and relative macrocephaly. She carries a paternally inherited approximately 2.1 Mb microduplication at distal 22q11.2, which spans approximately 34 annotated genes, and is flanked by two of the four telomeric 22q11.2 LCRs. We conclude that the four telomeric LCRs at distal 22q11.2 can mediate both deletions and duplications in this genomic region. Both deletions and duplication of this region present with subtle clinical features including mild to moderate mental retardation, DD, and mild dysmorphic features., (Copyright (c) 2008 Wiley-Liss, Inc.)

Here we report on a patient with an interstitial deletion on the long(q) arm of chromosome 1 who presents with a unique constellation of anomalies including brachydactyly type E, Müllerian agenesis, growth hormone deficiency, as well as other abnormalities. We present the clinical details of this patient's presentation, the skeletal findings, and provide characterization of the deletion at the molecular level. We postulate that these skeletal anomalies are distinctive to 1q deletions involving the 1q24q25 region., ((c) 2008 Wiley-Liss, Inc.)

Beckwith-Wiedemann syndrome (BWS) is clinically and molecularly very heterogenous. Molecular findings characteristic of BWS have been reported in individuals with no or few associated features. We report on a child with isolated cardiac tumor and a constitutional H19 hypermethylation with none of the features of BWS., (Copyright 2008 Wiley-Liss, Inc.)

Autism is a neurodevelopmental disorder of complex etiology in which genetic factors play a major role. We have implicated the neurexin 1 (NRXN1) gene in two independent subjects who display an autism spectrum disorder (ASD) in association with a balanced chromosomal abnormality involving 2p16.3. In the first, with karyotype 46,XX,ins(16;2)(q22.1;p16.1p16.3)pat, NRXN1 is directly disrupted within intron 5. Importantly, the father possesses the same chromosomal abnormality in the absence of ASD, indicating that the interruption of alpha-NRXN1 is not fully penetrant and must interact with other factors to produce ASD. The breakpoint in the second subject, with 46,XY,t(1;2)(q31.3;p16.3)dn, occurs approximately 750 kb 5' to NRXN1 within a 2.6 Mb genomic segment that harbors no currently annotated genes. A scan of the NRXN1 coding sequence in a cohort of ASD subjects, relative to non-ASD controls, revealed that amino acid alterations in neurexin 1 are not present at high frequency in ASD. However, a number of rare sequence variants in the coding region, including two missense changes in conserved residues of the alpha-neurexin 1 leader sequence and of an epidermal growth factor (EGF)-like domain, respectively, suggest that even subtle changes in NRXN1 might contribute to susceptibility to ASD.

Susceptibility of the chromosome 22q11.2 region to rearrangements has been recognized on the basis of common clinical disorders such as the DiGeorge/velocardiofacial syndrome (DG/VCFs). Recent evidence has implicated low-copy repeats (LCRs); also known as segmental duplications; on 22q as mediators of nonallelic homologous recombination (NAHR) that result in rearrangements of 22q11.2. It has been shown that both deletion and duplication events can occur as a result of NAHR caused by unequal crossover of LCRs. Here we report on the clinical, cytogenetic and array CGH studies of a 15-year-old Hispanic boy with history of learning and behavior problems. We suggest that he represents a previously unrecognized microdeletion syndrome on chromosome 22 band q11.2 just telomeric to the DG/VCFs typically deleted region and encompassing the BCR gene. Using a 32K BAC array CGH chip we were able to refine and precisely narrow the breakpoints of this microdeletion, which was estimated to be 1.55-1.92 Mb in size and to span approximately 20 genes. This microdeletion region is flanked by LCR clusters containing several modules with a very high degree of sequence homology (>95%), and therefore could play a causal role in its origin., ((c) 2007 Wiley-Liss, Inc.)

A report of the sixth case with the oculoauriculovertebral phenotype with limb anomalies and 5p terminal deletion is described.

Introduction: Isotretinoin (RA), used for the treatment of cystic acne, is a powerful teratogen, causing craniofacial dysmorphisms and neural tube defects. We present two patients with RA embryopathy and oculomotor nerve synkinesis., Methods: Retrospective review of patient records., Results: Two patients presented with third nerve synkinesis and fetal RA exposure. Both had marked elevation of the upper eyelids on adduction such that the lid fissures alternately opened and closed on gaze from side to side. Both patients showed typical dysmorphisms of RA embryopathy. The first patient had complete agenesis of the cerebellar vermix and died at 2 years. The second patient had restricted extraocular muscles in one eye and was exotropic and hypotropic., Discussion: Both patients demonstrated simultaneous innervation of the medial rectus and levator palpebrae muscles causing coincident lid elevation in adduction. This evidence of oculomotor nerve synkinesis is consistent with animal studies showing abnormalities in the formation of cranial nerve ganglia following fetal RA exposure., Conclusion: RA is a powerful teratogen. These patients provide additional clinical evidence of its influence on neural migration during early development.

We report on a mother and child with a paracentric inversion of the long arm of chromosome 18: 46,XX,inv(18)(q21.1q23). The child had findings in common with those seen in 18q- syndrome including: microcephaly, epicanthal folds, midface hypoplasia, and abnormally modeled ears, dermatoglyphic whorls on fingertips, clubfeet, hearing loss, and developmental delay. The mother and several maternal relatives had mild mental retardation and hearing loss. Magnetic resonance imaging of the child's brain showed abnormal myelination. Molecular studies including PCR-based markers for the MBP locus and fluorescent in situ hybridization with a P1 genomic clone on mother and child demonstrated only one copy of the MBP locus (18q23) with the deletion extending beyond the MBP locus. Therefore, the deletion in the MBP region may account for the abnormal myelination seen in the patient. The other clinical findings, including mental retardation and hearing loss in this family, may reflect disruption of distal or proximal genes within the deleted MBP region or at the more proximal breakpoint 18q21.1, and may represent a contiguous gene syndrome. Further study of this family may help define those genes functioning in the MBP region that contribute to the phenotype of 18q- syndrome.