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1.
Eur J Hum Genet ; 2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31395947

RESUMO

PTPN23 is a His-domain protein-tyrosine phosphatase implicated in ciliogenesis, the endosomal sorting complex required for transport (ESCRT) pathway, and RNA splicing. Until recently, no defined human phenotype had been associated with alterations in this gene. We identified and report a cohort of seven patients with either homozygous or compound heterozygous rare deleterious variants in PTPN23. Combined with four patients previously reported, a total of 11 patients with this disorder have now been identified. We expand the phenotypic and variation spectrum associated with defects in this gene. Patients have strong phenotypic overlap, suggesting a defined autosomal recessive syndrome caused by reduced function of PTPN23. Shared characteristics of affected individuals include developmental delay, brain abnormalities (mainly ventriculomegaly and/or brain atrophy), intellectual disability, spasticity, language disorder, microcephaly, optic atrophy, and seizures. We observe a broad range of variants across patients that are likely strongly reducing the expression or disrupting the function of the protein. However, we do not observe any patients with an allele combination predicted to result in complete loss of function of PTPN23, as this is likely incompatible with life, consistent with reported embryonic lethality in the mouse. None of the observed or reported variants are recurrent, although some have been identified in homozygosis in patients from consanguineous populations. This study expands the phenotypic and molecular spectrum of PTPN23 associated disease and identifies major shared features among patients affected with this disorder, while providing additional support to the important role of PTPN23 in human nervous and visual system development and function.

2.
Channels (Austin) ; 13(1): 153-161, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31070086

RESUMO

Neuromuscular disorders encompass a wide range of conditions often associated with a genetic component. In the present study, we report a patient with severe infantile-onset amyotrophy in whom two compound heterozygous variants in the gene CACNA1H encoding for Cav3.2 T-type calcium channels were identified. Functional analysis of Cav3.2 variants revealed several alterations of the gating properties of the channel that were in general consistent with a loss-of-channel function. Taken together, these findings suggest that severe congenital amyoplasia may be related to CACNA1H and would represent a new phenotype associated with mutations in this gene.

3.
Clin Genet ; 95(5): 601-606, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30790272

RESUMO

The GTPBP2 gene encodes a guanosine triphosphate (GTP)-binding protein of unknown function. Biallelic loss-of-function variants in the GTPBP2 gene have been previously reported in association with a neuro-ectodermal clinical presentation in six individuals from four unrelated families. Here, we provide detailed descriptions of three additional individuals from two unrelated families in the context of the previous literature. Both families carry nonsense variants in GTPBP2: homozygous p.(Arg470*) and compound heterozygous p.(Arg432*)/p.(Arg131*). Key features of this clinically recognizable condition include prenatal onset microcephaly, tone abnormalities, and movement disorders, epilepsy, dysmorphic features, retinal dysfunction, ectodermal dysplasia, and brain iron accumulation. Our findings suggest that some aspects of the clinical presentation appear to be age-related; brain iron accumulation may appear only after childhood, and the ectodermal findings and peripheral neuropathy are most prominent in older individuals. In addition, we present prenatal and neonatal findings as well as the first Caucasian and black African families with GTPBP2 biallelic variants. The individuals described herein provide valuable additional phenotypic information about this rare, novel, and progressive neuroectodermal condition.

5.
Dev Med Child Neurol ; 60(11): 1093-1100, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29992541

RESUMO

AIM: The Modified Checklist for Autism in Toddlers (M-CHAT) could be appropriate for universal screening for autism spectrum disorder (ASD) at 18 months and 24 months. Validation studies, however, reported differences in psychometric properties across sample populations. This meta-analysis summarized its accuracy measures and quantified their change in relation to patient and study characteristics. METHOD: Four electronic databases (MEDLINE, PsycINFO, CINAHL, and Embase) were searched to identify articles published between January 2001 and May 2016. Bayesian regression models pooled study-specific measures. Meta-regressions covariates were age at screening, study design, and proportion of males. RESULTS: On the basis of the 13 studies included, the pooled sensitivity was 0.83 (95% credible interval [CI] 0.75-0.90), specificity was 0.51 (95% CI 0.41-0.61), and positive predictive value was 0.53 (95% CI 0.43-0.63) in high-risk children and 0.06 (95% CI <0.01-0.14) in low-risk children. Sensitivity was higher for screening at 30 months compared with 24 months. INTERPRETATION: Findings indicate that the M-CHAT performs with low to moderate accuracy in identifying ASD among children with developmental concerns, but there was a lack of evidence on its performance in low-risk children or at age 18 months. Clinicians should account for a child's age and presence of developmental concern when interpreting their M-CHAT score. WHAT THIS PAPER ADDS: The Modified Checklist for Autism in Toddlers (M-CHAT) performs with low-to-moderate accuracy in children with developmental concerns. There is limited evidence supporting its use at 18 months or in low-risk children.


Assuntos
Transtorno Autístico/diagnóstico , Pré-Escolar , Humanos , Lactente
6.
Appl Health Econ Health Policy ; 16(4): 481-493, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29651777

RESUMO

BACKGROUND: Genome (GS) and exome sequencing (ES) could potentially identify pathogenic variants with greater sensitivity than chromosomal microarray (CMA) in autism spectrum disorder (ASD) but are costlier and result interpretation can be uncertain. Study objective was to compare the costs and outcomes of four genetic testing strategies in children with ASD. METHODS: A microsimulation model estimated the outcomes and costs (in societal and public payer perspectives in Ontario, Canada) of four genetic testing strategies: CMA for all, CMA for all followed by ES for those with negative CMA and syndromic features (CMA+ES), ES or GS for all. RESULTS: Compared to CMA, the incremental cost-effectiveness ratio (ICER) per additional child identified with rare pathogenic variants within 18 months of ASD diagnosis was $CAN5997.8 for CMA+ES, $CAN13,504.2 for ES and $CAN10,784.5 for GS in the societal perspective. ICERs were sensitive to changes in ES or GS diagnostic yields, wait times for test results or pre-test genetic counselling, but were robust to changes in the ES or GS costs. CONCLUSION: Strategic integration of ES into ASD care could be a cost-effective strategy. Long wait times for genetic services and uncertain utility, both clinical and personal, of sequencing results could limit broader clinical implementation.

7.
J Autism Dev Disord ; 48(9): 2968-2979, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29644584

RESUMO

The American Academy of Pediatrics recommends universal screening for autism spectrum disorder at 18 and 24 months. This study compared the cost-effectiveness of universal or high-risk screening to surveillance monitoring. Simulation models estimated the costs and outcomes from birth to age 6 years. The incremental cost per child diagnosed by 36 months was $41,651.6 for high-risk screening and $757,116.9 for universal screening from the societal perspective. Universal screening may not be a cost-effective approach to increase earlier treatment initiation, as most children initiated treatment after age 60 months. Eliminating wait times resulted in more children initiated treatment by 48 months, but at a high initial cost that may be offset by future cost-savings related to better outcomes.

8.
Hum Mutat ; 39(5): 666-675, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29330883

RESUMO

Heterozygous variants in the arginine-glutamic acid dipeptide repeats gene (RERE) have been shown to cause neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (NEDBEH). Here, we report nine individuals with NEDBEH who carry partial deletions or deleterious sequence variants in RERE. These variants were found to be de novo in all cases in which parental samples were available. An analysis of data from individuals with NEDBEH suggests that point mutations affecting the Atrophin-1 domain of RERE are associated with an increased risk of structural eye defects, congenital heart defects, renal anomalies, and sensorineural hearing loss when compared with loss-of-function variants that are likely to lead to haploinsufficiency. A high percentage of RERE pathogenic variants affect a histidine-rich region in the Atrophin-1 domain. We have also identified a recurrent two-amino-acid duplication in this region that is associated with the development of a CHARGE syndrome-like phenotype. We conclude that mutations affecting RERE result in a spectrum of clinical phenotypes. Genotype-phenotype correlations exist and can be used to guide medical decision making. Consideration should also be given to screening for RERE variants in individuals who fulfill diagnostic criteria for CHARGE syndrome but do not carry pathogenic variants in CHD7.

9.
Genet Med ; 20(4): 435-443, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28771251

RESUMO

PurposeGenetic testing is an integral diagnostic component of pediatric medicine. Standard of care is often a time-consuming stepwise approach involving chromosomal microarray analysis and targeted gene sequencing panels, which can be costly and inconclusive. Whole-genome sequencing (WGS) provides a comprehensive testing platform that has the potential to streamline genetic assessments, but there are limited comparative data to guide its clinical use.MethodsWe prospectively recruited 103 patients from pediatric non-genetic subspecialty clinics, each with a clinical phenotype suggestive of an underlying genetic disorder, and compared the diagnostic yield and coverage of WGS with those of conventional genetic testing.ResultsWGS identified diagnostic variants in 41% of individuals, representing a significant increase over conventional testing results (24%; P = 0.01). Genes clinically sequenced in the cohort (n = 1,226) were well covered by WGS, with a median exonic coverage of 40 × ±8 × (mean ±SD). All the molecular diagnoses made by conventional methods were captured by WGS. The 18 new diagnoses made with WGS included structural and non-exonic sequence variants not detectable with whole-exome sequencing, and confirmed recent disease associations with the genes PIGG, RNU4ATAC, TRIO, and UNC13A.ConclusionWGS as a primary clinical test provided a higher diagnostic yield than conventional genetic testing in a clinically heterogeneous cohort.


Assuntos
Estudos de Associação Genética , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Predisposição Genética para Doença , Testes Genéticos , Análise de Sequência de DNA , Sequenciamento Completo do Genoma , Biologia Computacional/métodos , Variações do Número de Cópias de DNA , Exoma , Feminino , Estudos de Associação Genética/métodos , Estudos de Associação Genética/normas , Testes Genéticos/métodos , Testes Genéticos/normas , Variação Genética , Humanos , Masculino , Anotação de Sequência Molecular , Fenótipo , Análise de Sequência de DNA/métodos , Análise de Sequência de DNA/normas , Sequenciamento Completo do Exoma/métodos , Sequenciamento Completo do Exoma/normas , Sequenciamento Completo do Genoma/métodos , Sequenciamento Completo do Genoma/normas
10.
NPJ Genom Med ; 2: 28, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29263838

RESUMO

Duplication of chromosome 22q11.2 (LCR A-D) has been reported at higher frequencies in clinical samples than the general population, but phenotypes vary widely. Triplication (4 copies) is rare, but studying the associated phenotype may provide insight into dosage-sensitivity of the genes in this chromosomal interval. We describe a proband with a triplication, specifically a "double duplication" (two copies per chromosome) of the 22q11.2 region, while his parents and two siblings each have a single duplication (3 copies). The proband had a heart malformation, dysmorphic features, and learning and socialization deficits, whereas the other family members did not. This family illustrates that while duplication of the 22q11.2 may not be sufficient to cause clinically significant neurodevelopmental or health-related phenotypes, triplication of the same region may result in a phenotype characterized by a mild neurodevelopmental disorder, facial dysmorphism, and possibly cardiac anomalies.

11.
Am J Med Genet A ; 173(11): 3082-3086, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28980384

RESUMO

Walker-Warburg syndrome (WWS) is a rare autosomal recessive, congenital muscular dystrophy that is associated with brain and eye anomalies. Several genes encoding proteins involved in α-dystroglycan glycosylation have been implicated in the aetiology of WWS. We describe a patient with nonclassical features of WWS presenting with heart failure related to noncompaction cardiomyopathy resulting in death at 4 months of age. Muscle biopsy revealed absent α-dystroglycan on immunostaining and genetic testing confirmed the diagnosis with two previously described POMT2 mutations. This is the first reported case of WWS syndrome associated with noncompaction cardiomyopathy.


Assuntos
Cardiomiopatias/genética , Anormalidades do Olho/genética , Manosiltransferases/genética , Síndrome de Walker-Warburg/genética , Encéfalo/patologia , Cardiomiopatias/complicações , Cardiomiopatias/diagnóstico , Cardiomiopatias/patologia , Anormalidades do Olho/patologia , Predisposição Genética para Doença , Humanos , Lactente , Masculino , Mutação , Linhagem , Síndrome de Walker-Warburg/complicações , Síndrome de Walker-Warburg/diagnóstico , Síndrome de Walker-Warburg/patologia
12.
Horm Res Paediatr ; 88(3-4): 298-304, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28605746

RESUMO

BACKGROUND AND OBJECTIVES: Plastin 3 (PLS3) mutations are associated with an X-linked osteoporosis. Here we describe two new families with novel mutations, including one with a whole gene PLS3 deletion, and review the literature on 9 previously reported cases. RESULTS: Hemizygous male carriers presented with multiple peripheral bone fractures, low bone mineral density (BMD), and vertebral compression fractures. Heterozygous female carriers did not have a history of fragility fractures, although 1 individual presented with low BMD. Apart from greyish-tinged sclera, no other extraskeletal features of osteogenesis imperfecta were identified. Histomorphometry from a transiliac bone biopsy in one of our index patients demonstrated significantly low trabecular bone volume with increased bone turnover. Bisphosphonate treatment was associated with a reduction in the fracture rate and increased bone density. CONCLUSION: Hemizygous mutations in PLS3 may cause a monogenic form of X-linked osteoporosis presenting in childhood with a nonspecific phenotype. No characteristic ocular, dental, or joint abnormalities are defined. When genetic testing is undertaken to investigate for primary causes of bone fragility, we suggest PLS3 be included in order not to miss this diagnosis.


Assuntos
Glicoproteínas de Membrana/genética , Proteínas dos Microfilamentos/genética , Mutação , Osteoporose/genética , Densidade Óssea/genética , Criança , Pré-Escolar , Humanos , Masculino , Linhagem
13.
Am J Med Genet A ; 173(2): 395-406, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27759917

RESUMO

We performed whole-genome sequencing on an individual from a family with variable psychiatric phenotypes that had a sensory processing disorder, apraxia, and autism. The proband harbored a maternally inherited balanced translocation (46,XY,t(11;14)(p12;p12)mat) that disrupted LRRC4C, a member of the highly specialized netrin G family of axon guidance molecules. The proband also inherited a paternally derived chromosomal inversion that disrupted DPP6, a potassium channel interacting protein. Copy Number (CN) analysis in 14,077 cases with neurodevelopmental disorders and 8,960 control subjects revealed that 60% of cases with exonic deletions in LRRC4C had a second clinically recognizable syndrome associated with variable clinical phenotypes, including 16p11.2, 1q44, and 2q33.1 CN syndromes, suggesting LRRC4C deletion variants may be modifiers of neurodevelopmental disorders. In vitro, functional assessments modeling patient deletions in LRRC4C suggest a negative regulatory role of these exons found in the untranslated region of LRRC4C, which has a single, terminal coding exon. These data suggest that the proband's autism may be due to the inheritance of disruptions in both DPP6 and LRRC4C, and may highlight the importance of the netrin G family and potassium channel interacting molecules in neurodevelopmental disorders. © 2016 Wiley Periodicals, Inc.


Assuntos
Dipeptidil Peptidases e Tripeptidil Peptidases/genética , Estudos de Associação Genética , Proteínas do Tecido Nervoso/genética , Transtornos do Neurodesenvolvimento/diagnóstico , Transtornos do Neurodesenvolvimento/genética , Fenótipo , Canais de Potássio/genética , Receptores de Superfície Celular/genética , Regiões 5' não Traduzidas , Adolescente , Adulto , Apraxias/diagnóstico , Apraxias/genética , Transtorno Autístico/diagnóstico , Transtorno Autístico/genética , Criança , Pré-Escolar , Pontos de Quebra do Cromossomo , Inversão Cromossômica , Hibridização Genômica Comparativa , Variações do Número de Cópias de DNA , Feminino , Expressão Gênica , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Cariótipo , Masculino , Pessoa de Meia-Idade , Família Multigênica , Linhagem , Translocação Genética , Adulto Jovem
14.
Am J Med Genet A ; 170(11): 3018-3022, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27531570

RESUMO

We describe two brothers from a consanguineous family of Egyptian ancestry, presenting with microcephaly, apparent global developmental delay, seizures, spasticity, congenital blindness, and multiple cutaneous capillary malformations. Through exome sequencing, we uncovered a homozygous missense variant in STAMBP (p.K303R) in the two siblings, inherited from heterozygous carrier parents. Mutations in STAMBP are known to cause microcephaly-capillary malformation syndrome (MIC-CAP) and the phenotype in this family is consistent with this diagnosis. We compared the findings in the present brothers with those of earlier reported patients. © 2016 Wiley Periodicals, Inc.


Assuntos
Capilares/anormalidades , Complexos Endossomais de Distribuição Requeridos para Transporte/genética , Homozigoto , Microcefalia/diagnóstico , Microcefalia/genética , Ubiquitina Tiolesterase/genética , Malformações Vasculares/diagnóstico , Malformações Vasculares/genética , Encéfalo/patologia , Consanguinidade , Variações do Número de Cópias de DNA , Análise Mutacional de DNA , Exoma , Facies , Estudos de Associação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imagem por Ressonância Magnética , Masculino , Mutação , Linhagem , Fenótipo , Irmãos , Síndrome
15.
Sci Rep ; 6: 28663, 2016 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-27363808

RESUMO

A challenge in clinical genomics is to predict whether copy number variation (CNV) affecting a gene or multiple genes will manifest as disease. Increasing recognition of gene dosage effects in neurodevelopmental disorders prompted us to develop a computational approach based on critical-exon (highly expressed in brain, highly conserved) examination for potential etiologic effects. Using a large CNV dataset, our updated analyses revealed significant (P < 1.64 × 10(-15)) enrichment of critical-exons within rare CNVs in cases compared to controls. Separately, we used a weighted gene co-expression network analysis (WGCNA) to construct an unbiased protein module from prenatal and adult tissues and found it significantly enriched for critical exons in prenatal (P < 1.15 × 10(-50), OR = 2.11) and adult (P < 6.03 × 10(-18), OR = 1.55) tissues. WGCNA yielded 1,206 proteins for which we prioritized the corresponding genes as likely to have a role in neurodevelopmental disorders. We compared the gene lists obtained from critical-exon and WGCNA analysis and found 438 candidate genes associated with CNVs annotated as pathogenic, or as variants of uncertain significance (VOUS), from among 10,619 developmental delay cases. We identified genes containing CNVs previously considered to be VOUS to be new candidate genes for neurodevelopmental disorders (GIT1, MVB12B and PPP1R9A) demonstrating the utility of this strategy to index the clinical effects of CNVs.


Assuntos
Variações do Número de Cópias de DNA , Deficiências do Desenvolvimento/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adulto , Encéfalo/embriologia , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Criança , Deficiências do Desenvolvimento/metabolismo , Feminino , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Masculino , Proteômica/métodos
16.
Am J Med Genet A ; 170A(4): 1070-5, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26754023

RESUMO

Lateral meningocele syndrome (LMS), or Lehman syndrome, is a rare disorder characterized by multiple lateral spinal meningoceles, distinctive facial features, joint hypermobility and hypotonia, along with skeletal, cardiac, and urogenital anomalies. Heterozygous NOTCH3 mutations affecting the terminal exon 33 were recently reported as causative in six families with LMS. We report a boy with LMS, the fourteenth reported case, with a de novo 80 base pair deletion in exon 33 of NOTCH3. Our patient's prenatal findings, complex cardiac anomalies, and severe feeding difficulties further expand our understanding of this rare condition.


Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Meningocele/diagnóstico , Meningocele/genética , Mutação , Receptor Notch3/genética , Encéfalo/patologia , Pré-Escolar , Análise Mutacional de DNA , Éxons , Facies , Humanos , Imagem por Ressonância Magnética , Masculino , Neuroimagem , Fenótipo
17.
NPJ Genom Med ; 12016 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-28567303

RESUMO

The standard of care for first-tier clinical investigation of the etiology of congenital malformations and neurodevelopmental disorders is chromosome microarray analysis (CMA) for copy number variations (CNVs), often followed by gene(s)-specific sequencing searching for smaller insertion-deletions (indels) and single nucleotide variant (SNV) mutations. Whole genome sequencing (WGS) has the potential to capture all classes of genetic variation in one experiment; however, the diagnostic yield for mutation detection of WGS compared to CMA, and other tests, needs to be established. In a prospective study we utilized WGS and comprehensive medical annotation to assess 100 patients referred to a paediatric genetics service and compared the diagnostic yield versus standard genetic testing. WGS identified genetic variants meeting clinical diagnostic criteria in 34% of cases, representing a 4-fold increase in diagnostic rate over CMA (8%) (p-value = 1.42e-05) alone and >2-fold increase in CMA plus targeted gene sequencing (13%) (p-value = 0.0009). WGS identified all rare clinically significant CNVs that were detected by CMA. In 26 patients, WGS revealed indel and missense mutations presenting in a dominant (63%) or a recessive (37%) manner. We found four subjects with mutations in at least two genes associated with distinct genetic disorders, including two cases harboring a pathogenic CNV and SNV. When considering medically actionable secondary findings in addition to primary WGS findings, 38% of patients would benefit from genetic counseling. Clinical implementation of WGS as a primary test will provide a higher diagnostic yield than conventional genetic testing and potentially reduce the time required to reach a genetic diagnosis.

18.
Psychiatr Genet ; 26(2): 66-73, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26529358

RESUMO

Non-syndromic autosomal recessive intellectual disability (ID) is a genetically heterogeneous disorder with more than 50 mutated genes to date. ID is characterized by deficits in memory skills and language development with difficulty in learning, problem solving, and adaptive behaviors, and affects ∼ 1% of the population. For detection of disease-causing mutations in such a heterogeneous disorder, homozygosity mapping together with exome sequencing is a powerful approach, as almost all known genes can be assessed simultaneously in a high-throughput manner. In this study, a hemizygous c.786C>G:p.Ile262Met in the testis specific protein Y-encoded-like 2 (TSPYL2) gene and a homozygous c.11335G>A:p.Asp3779Asn in the low-density lipoprotein receptor-related protein 2 (LRP2) gene were detected after genome-wide genotyping and exome sequencing in a consanguineous Pakistani family with two boys with mild ID. Mutations in the LRP2 gene have previously been reported in patients with Donnai-Barrow and Stickler syndromes. LRP2 has also been associated with a 2q locus for autism (AUTS5). The TSPYL2 variant is not listed in any single-nucleotide polymorphism databases, and the LRP2 variant was absent in 400 ethnically matched healthy control chromosomes, and is not listed in single-nucleotide polymorphism databases as a common polymorphism. The LRP2 mutation identified here is located in one of the low-density lipoprotein-receptor class A domains, which is a cysteine-rich repeat that plays a central role in mammalian cholesterol metabolism, suggesting that alteration of cholesterol processing pathway can contribute to ID.


Assuntos
Deficiência Intelectual/genética , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Proteínas Nucleares/genética , Grupo com Ancestrais do Continente Asiático , Exoma , Feminino , Genes Recessivos , Ligação Genética , Homozigoto , Humanos , Masculino , Mutação de Sentido Incorreto , Paquistão , Linhagem
19.
Am J Med Genet A ; 170(3): 712-6, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26647099

RESUMO

The 16p12 region is particularly prone to genomic disorders due to the large number of low copy repeats [Martin et al., 2004; Nature 432:988-994]. We report two unrelated patients with de novo triplication of 16p12.1p12.3 who had developmental delay and similar facial features. Patient 1 is a 4-year-old male with a congenital heart anomaly, bilateral cryptorchidism, chronic constipation, and developmental delay. Patient 2 is a 12-year-old female with prenatally diagnosed hydronephrosis, hepatobiliary disease, failure to thrive, and developmental delay. Distinctive facial features common to both patients include short palpebral fissures, bulbous nose, thin upper vermillion border, apparently lowset ears, and large ear lobes. We compare the clinical manifestations of our patients with a previously reported patient with triplication of 16p12.2.


Assuntos
Cromossomos Humanos Par 16 , Cromossomos Humanos Par 1 , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Facies , Trissomia , Criança , Pré-Escolar , Hibridização Genômica Comparativa , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Hibridização in Situ Fluorescente , Lactente , Masculino , Fenótipo
20.
JAMA ; 314(9): 895-903, 2015 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-26325558

RESUMO

IMPORTANCE: The use of genome-wide tests to provide molecular diagnosis for individuals with autism spectrum disorder (ASD) requires more study. OBJECTIVE: To perform chromosomal microarray analysis (CMA) and whole-exome sequencing (WES) in a heterogeneous group of children with ASD to determine the molecular diagnostic yield of these tests in a sample typical of a developmental pediatric clinic. DESIGN, SETTING, AND PARTICIPANTS: The sample consisted of 258 consecutively ascertained unrelated children with ASD who underwent detailed assessments to define morphology scores based on the presence of major congenital abnormalities and minor physical anomalies. The children were recruited between 2008 and 2013 in Newfoundland and Labrador, Canada. The probands were stratified into 3 groups of increasing morphological severity: essential, equivocal, and complex (scores of 0-3, 4-5, and ≥6). EXPOSURES: All probands underwent CMA, with WES performed for 95 proband-parent trios. MAIN OUTCOMES AND MEASURES: The overall molecular diagnostic yield for CMA and WES in a population-based ASD sample stratified in 3 phenotypic groups. RESULTS: Of 258 probands, 24 (9.3%, 95%CI, 6.1%-13.5%) received a molecular diagnosis from CMA and 8 of 95 (8.4%, 95%CI, 3.7%-15.9%) from WES. The yields were statistically different between the morphological groups. Among the children who underwent both CMA and WES testing, the estimated proportion with an identifiable genetic etiology was 15.8% (95%CI, 9.1%-24.7%; 15/95 children). This included 2 children who received molecular diagnoses from both tests. The combined yield was significantly higher in the complex group when compared with the essential group (pairwise comparison, P = .002). [table: see text]. CONCLUSIONS AND RELEVANCE: Among a heterogeneous sample of children with ASD, the molecular diagnostic yields of CMA and WES were comparable, and the combined molecular diagnostic yield was higher in children with more complex morphological phenotypes in comparison with the children in the essential category. If replicated in additional populations, these findings may inform appropriate selection of molecular diagnostic testing for children affected by ASD.


Assuntos
Transtornos Globais do Desenvolvimento Infantil/genética , Exoma , Análise em Microsséries/métodos , Técnicas de Diagnóstico Molecular/métodos , Síndrome de Asperger/diagnóstico , Síndrome de Asperger/genética , Transtorno Autístico/diagnóstico , Transtorno Autístico/genética , Criança , Transtornos Globais do Desenvolvimento Infantil/diagnóstico , Transtornos Globais do Desenvolvimento Infantil/patologia , Pré-Escolar , Feminino , Humanos , Masculino , Análise em Microsséries/estatística & dados numéricos , Técnicas de Diagnóstico Molecular/estatística & dados numéricos , Mutação , Análise de Sequência com Séries de Oligonucleotídeos/estatística & dados numéricos , Fenótipo , Análise de Sequência de DNA/métodos , Análise de Sequência de Proteína/métodos
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