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1.
Genome Med ; 11(1): 68, 2019 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-31694722

RESUMO

BACKGROUND: Since different types of genetic variants, from single nucleotide variants (SNVs) to large chromosomal rearrangements, underlie intellectual disability, we evaluated the use of whole-genome sequencing (WGS) rather than chromosomal microarray analysis (CMA) as a first-line genetic diagnostic test. METHODS: We analyzed three cohorts with short-read WGS: (i) a retrospective cohort with validated copy number variants (CNVs) (cohort 1, n = 68), (ii) individuals referred for monogenic multi-gene panels (cohort 2, n = 156), and (iii) 100 prospective, consecutive cases referred to our center for CMA (cohort 3). Bioinformatic tools developed include FindSV, SVDB, Rhocall, Rhoviz, and vcf2cytosure. RESULTS: First, we validated our structural variant (SV)-calling pipeline on cohort 1, consisting of three trisomies and 79 deletions and duplications with a median size of 850 kb (min 500 bp, max 155 Mb). All variants were detected. Second, we utilized the same pipeline in cohort 2 and analyzed with monogenic WGS panels, increasing the diagnostic yield to 8%. Next, cohort 3 was analyzed by both CMA and WGS. The WGS data was processed for large (> 10 kb) SVs genome-wide and for exonic SVs and SNVs in a panel of 887 genes linked to intellectual disability as well as genes matched to patient-specific Human Phenotype Ontology (HPO) phenotypes. This yielded a total of 25 pathogenic variants (SNVs or SVs), of which 12 were detected by CMA as well. We also applied short tandem repeat (STR) expansion detection and discovered one pathologic expansion in ATXN7. Finally, a case of Prader-Willi syndrome with uniparental disomy (UPD) was validated in the WGS data. Important positional information was obtained in all cohorts. Remarkably, 7% of the analyzed cases harbored complex structural variants, as exemplified by a ring chromosome and two duplications found to be an insertional translocation and part of a cryptic unbalanced translocation, respectively. CONCLUSION: The overall diagnostic rate of 27% was more than doubled compared to clinical microarray (12%). Using WGS, we detected a wide range of SVs with high accuracy. Since the WGS data also allowed for analysis of SNVs, UPD, and STRs, it represents a powerful comprehensive genetic test in a clinical diagnostic laboratory setting.

2.
Mol Genet Genomic Med ; : e1013, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31730283

RESUMO

BACKGROUND: Variable size deletions affecting 12q12 have been found in individuals with neurodevelopmental disorders (NDDs) and distinct facial and physical features. For many genetic loci affected by deletions in individuals with NDDs, reciprocal duplications have been described. However, for the 12q12 region, there are no detailed descriptions of duplication cases in the literature. METHODS: We report a phenotypic description of a family with monozygotic twins diagnosed with NDDs, carrying a 9 Mb duplication at 12q12, and five other individuals with overlapping duplications ranging from 4.54 Mb up to 15.16 Mb. RESULTS: The duplication carriers had language delays, cognitive delays, and were diagnosed with autism spectrum disorder. Additionally, distinct facial features (e.g., high foreheads, deeply set eyes, short palpebral fissures, small ears, high nasal bridges, abnormalities of the nose tip, thin lips), large feet, and abnormalities in the digits were noted. We also describe incomplete penetrance of the NDD phenotypes among the individuals with 12q12 duplication. CONCLUSION: This case series expands our knowledge on this rare genetic aberration and suggests that large 12q12 duplications may increase the risk for developing NDDs.

3.
Autism Res ; 2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31593375

RESUMO

Autism spectrum disorders (ASD) comprises heterogeneous neurodevelopmental conditions with symptom onset usually during infancy. However, about 10%-30% of affected cases experience a loss of language and social skills around 18-30 months, so-called regressive autism. In this subset with regression, immune dysfunctions including inflammation and autoimmunity have been proposed to be at risk factors. Given the implication of the human histocompatibility antigens (HLA) system in various aspects of immune responses, including autoimmunity, and in ASD, we investigate here the distribution of the HLA Class I and Class II haplotypes in 131 children with ASD meeting DSM-IV TR criteria, with and without regression. We found that 62 of the 98 non-regressive ASD patients carry the HLA-DPA1*01-DPB1*04 sub-haplotype as compared to 14 of the 33 patients with regression (63% vs. 43% respectively, Pc = 0.02), suggesting that this HLA haplotype may exert a protective effect against regression. Similarly, the HLA-DPA1*01-DPB1*04 has also been found to be more represented in healthy controls as compared to patients affected with common nonpsychiatric autoimmune disorders. Overall our findings suggest a possible involvement of HLA polymorphism in the context of regressive ASD. © 2019 The Authors. Autism Research published by International Society for Autism Research published by Wiley Periodicals, Inc. LAY SUMMARY: Immune dysfunctions including inflammatory and autoimmune processes have been reported in autism, particularly in regressive forms. In this study, we analyzed the distribution of HLA haplotypes among children with autism spectrum disorder (ASD), with and without regression from Sweden and observed that HLA-DPA1*01-DPB1*04 sub-haplotype was less represented in patients with regressive autism as compared with those without regression. Such possible protective effect, also observed in other common autoimmune disorders, may constitute a link between HLA-mediated immune processes and regressive ASD.

4.
Stem Cell Res ; 39: 101518, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31376723

RESUMO

Mowat-Wilson syndrome (MWS) is a complex developmental syndrome caused by heterozygous mutations in the Zinc finger E-box-binding homeobox 2 gene (ZEB2). We generated the first human iPSC lines from primary fibroblasts of two siblings with MWS carrying a heterozygous ZEB2 stop mutation (c.1027C > T; p.Arg343*) using the Sendai virus reprogramming system. Both iPSC lines were free from reprogramming vector genes, expressed pluripotency markers and showed potential to differentiate into the three germ layers. Genetic analysis confirmed normal karyotypes and a preserved stop mutation. These iPSC lines will provide a useful resource to study altered neural lineage fate and neuropathophysiology in MWS.

5.
Exp Cell Res ; 383(1): 111469, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31302032

RESUMO

We generated human iPS derived neural stem cells and differentiated cells from healthy control individuals and an individual with autism spectrum disorder carrying bi-allelic NRXN1-alpha deletion. We investigated the expression of NRXN1-alpha during neural induction and neural differentiation and observed a pivotal role for NRXN1-alpha during early neural induction and neuronal differentiation. Single cell RNA-seq pinpointed neural stem cells carrying NRXN1-alpha deletion shifting towards radial glia-like cell identity and revealed higher proportion of differentiated astroglia. Furthermore, neuronal cells carrying NRXN1-alpha deletion were identified as immature by single cell RNA-seq analysis, displayed significant depression in calcium signaling activity and presented impaired maturation action potential profile in neurons investigated with electrophysiology. Our observations propose NRXN1-alpha plays an important role for the efficient establishment of neural stem cells, in neuronal differentiation and in maturation of functional excitatory neuronal cells.

6.
Am J Hum Genet ; 104(6): 1210-1222, 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31079897

RESUMO

We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities.

7.
Clin Genet ; 94(6): 528-537, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30221345

RESUMO

We have investigated 20 consanguineous families with multiple children affected by rare disorders. Detailed clinical examinations, exome sequencing of affected as well as unaffected family members and further validation of likely pathogenic variants were performed. In 16/20 families, we identified pathogenic variants in autosomal recessive disease genes (ALMS1, PIGT, FLVCR2, TFG, CYP7B1, ALG14, EXOSC3, MEGF10, ASAH1, WDR62, ASPM, PNPO, ERCC5, KIAA1109, RIPK4, MAN1B1). A number of these genes have only rarely been reported previously and our findings thus confirm them as disease genes, further delineate the associated phenotypes and expand the mutation spectrum with reports of novel variants. We highlight the findings in two affected siblings with splice altering variants in ALG14 and propose a new clinical entity, which includes severe intellectual disability, epilepsy, behavioral problems and mild dysmorphic features, caused by biallelic variants in ALG14.

8.
Dev Med Child Neurol ; 60(12): 1251-1255, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29956301

RESUMO

AIM: To elucidate the natural course of benign paroxysmal torticollis, the relationship of this disorder to migraine and other paroxysmal diseases, and to analyse candidate genes. METHOD: This was a case series of children with benign paroxysmal torticollis of infancy (BPTI) diagnosed from 1998 to 2005, at Astrid Lindgren Children's Hospital, Stockholm, Sweden. A neurological examination and a formalized motor assessment were performed from 2005 to 2007. At a second follow-up, in 2014 to 2015, the children and their parents were interviewed and candidate genes analysed. RESULTS: The mean age of the eight females and three males included in the second follow-up was 13 years 9 months (SD 2y 2mo). All motor assessments were normal. Five had developed migraine, abdominal migraine, and/or cyclic vomiting. Prophylactic treatment or migraine-specific medication during attacks were not needed. No paroxysmal tonic upgaze, benign paroxysmal vertigo, epilepsy, episodic ataxia, or paroxysmal dyskinesia was reported. Rare genetic variants in CACNA1A and ATP1A2 were found in two children. Five had a family history of migraine. INTERPRETATION: BPTI is transient and does not lead to neurological sequelae. Most children afflicted experience either a mild migraine or no paroxysmal disorder at all in their adolescence. Genetic variants in candidate genes were few, indicating potential genetic heterogeneity. WHAT THIS PAPER ADDS: After resolution of their benign paroxysmal torticollis of infancy (BPTI), children display no gross motor delay. Most adolescents who previously had BPTI have not developed migraine. No mutations in candidate genes, known to cause hemiplegic migraine, were found. Associated symptoms are often lacking during episodes of torticollis.

9.
Mol Genet Genomic Med ; 6(3): 393-400, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29573576

RESUMO

BACKGROUND: Patients with pathogenic variants in ZBTB18 present with Intellectual Disability (ID) with frequent co-occurrence of corpus callosum (CC) anomalies, hypotonia, microcephaly, growth problems and variable facial dysmorphologies. These features illustrate a key role for ZBTB18 in brain development. METHODS: Patients with a pathogenic variant in ZBTB18 were detected by diagnostic whole exome sequencing (WES) performed in our center. We reviewed the literature and used GeneMatcher to include other cases. YASARA and WHAT IF were used to provide insight into the structural effect of missense variants located in the C2H2 zinc finger domains of the ZBTB18 protein. RESULTS: We give a complete overview of pathogenic variants in ZBTB18 detected to date, showing inconsistent presence of clinical features, including CC anomalies. We present four new cases with a de novo pathogenic variant in the ZBTB18 gene, including the fourth case in which a de novo p.Arg464His variant was found. CONCLUSION: Homology modeling of protein structure points to a variable degree of impaired DNA binding caused by missense variants in these domains probably leading to Loss of Function (LoF). Putative partial LoF may present with a less distinctive phenotype than complete LoF, as seen in truncating variants, which presents with an extensive variability in the phenotypic spectrum. Our data do not support a clear genotype to phenotype correlation.


Assuntos
Proteínas Repressoras/genética , Proteínas Repressoras/fisiologia , Adolescente , Agenesia do Corpo Caloso/genética , Encéfalo/fisiopatologia , Criança , Pré-Escolar , Deleção Cromossômica , Corpo Caloso/patologia , Proteínas de Ligação a DNA/genética , Deficiências do Desenvolvimento/genética , Feminino , Estudos de Associação Genética , Humanos , Lactente , Deficiência Intelectual/genética , Masculino , Microcefalia/genética , Hipotonia Muscular/genética , Mutação , Sequenciamento Completo do Exoma/métodos
10.
Twin Res Hum Genet ; 21(1): 1-11, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29307321

RESUMO

Hundreds of penetrant risk loci have been identified across different neurodevelopmental disorders (NDDs), and these often involve rare (<1% frequency) copy number variations (CNVs), which can involve one or more genes. Monozygotic (MZ) twin pairs are long thought to share 100% of their genomic information. However, genetic differences in the form of postzygotic somatic variants have been reported recently both in typically developing (TD) and in clinically discordant MZ pairs. We sought to investigate the contribution of rare CNVs in 100 twin pairs enriched for NDD phenotypes with a particular focus on postzygotic CNVs in MZ pairs discordant for autism spectrum disorder (ASD) using the Illumina Infinium PsychArray. In our sample, no postzygotic de novo CNVs were found in 55 MZ twin pairs, including the 13 pairs discordant for ASD. We did detect a higher rate of CNVs overlapping genes involved in disorders of the nervous system, such as a rare deletion affecting HNRNPU, in MZ pairs discordant and concordant for ASD in comparison with TD pairs (p = .02). Our results are in concordance with earlier findings that postzygotic de novo CNV events are typically rare in genomic DNA derived from saliva or blood, and suggests that the discordance of NDDs in our sample of twins is not explained by discordant CNVs. Still, studies investigating postzygotic variation in MZ discordant twins using DNA from different tissues and single cells and higher resolution genomics are needed in the future.


Assuntos
Variações do Número de Cópias de DNA , Doenças em Gêmeos/genética , Transtornos do Neurodesenvolvimento/genética , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genética , Adolescente , Adulto , Transtorno do Espectro Autista/genética , Criança , Feminino , Humanos , Masculino , Suécia , Adulto Jovem
11.
Mol Autism ; 9: 1, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29321841

RESUMO

Background: A substantial amount of research shows a higher rate of autistic type of problems in males compared to females. The 4:1 male to female ratio is one of the most consistent findings in autism spectrum disorder (ASD).Lately, the interest in studying ASD in genetic disorders has increased, and research has shown a higher prevalence of ASD in some genetic disorders than in the general population.Smith-Magenis syndrome (SMS) is a rare and complex genetic syndrome caused by an interstitial deletion of chromosome 17p11.2 or a mutation on the retinoic acid induced 1 gene. The disorder is characterised by intellectual disability, multiple congenital anomalies, obesity, neurobehavioural abnormalities and a disrupted circadian sleep-wake pattern. Methods: Parents of 28 persons with SMS between 5 and 50 years old participated in this study. A total of 12 of the persons with SMS were above the age of 18 at the time of the study. A total of 11 came from Sweden and 17 were from Norway.We collected information regarding the number of autism spectrum symptoms using the Social Communication Questionnaire (SCQ) and the Social Responsiveness Scale (SRS). Adaptive behaviour was also measured using the Vineland Adaptive Behavior Scale II. The level of intellectual disability was derived from a review of the medical chart. Results: We found significant gender differences in ASD symptomatology using the SCQ and SRS questionnaires. We found approximately three females per male above the SCQ cutoff. The same differences were not found in the intellectual level and adaptive behaviour or for behavioural and emotional problems.Gender had an independent contribution in a regression model predicting the total SCQ score, and neither the Vineland Adaptive Behavior Scale II nor the Developmental Behaviour Checklist had an independent contribution to the SCQ scores. Conclusion: We found a clear reversed gender difference in ASD symptomatology in persons with SMS. This may be relevant in the search for female protective factors assumed to explain the male bias in ASD.


Assuntos
Transtorno do Espectro Autista/epidemiologia , Razão de Masculinidade , Síndrome de Smith-Magenis/complicações , Adolescente , Adulto , Transtorno do Espectro Autista/diagnóstico , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Síndrome de Smith-Magenis/diagnóstico
13.
Artigo em Inglês | MEDLINE | ID: mdl-29209412

RESUMO

Background: Minor physical anomalies (MPAs) are subtle anatomical deviations in one's appearance and may suggest altered embryogenesis. MPAs have been shown to be more common in neurodevelopmental disorders (NDDs) compared with typical development. Still, further studies are needed on MPAs in NDDs, especially using twins to adjust for confounding familial factors. Methods: Clinical assessments were conducted on 116 twins (61 NDD, 55 controls) from 51 monozygotic and 7 dizygotic pairs to examine MPAs and their association with DSM-5 defined NDDs. Additionally, the relationship between the number of MPAs within twins by zygosity was investigated. Results: Within the cohort sample, a specific association was found between MPAs and autism spectrum disorder (ASD) diagnosis (crude odds ratio = 1.29, p = .047; adjusted odds ratios = 1.26-1.33, adjusted p values = .032-.073) and autistic traits (crude ß = 3.02, p = .002; adjusted ß = 2.28, p = .019), but not NDDs in general or ADHD, nor within-pairs. Identified MPAs in ASD included overweight, hypermobility, pes planus, straight eyebrows, vision impairment, arachnodactyly/long toes, long eyelashes, and microtia. The number of MPAs within all monozygotic pairs was highly correlated (r = .88, p < .001). Conclusion: MPAs are more frequent in participants with ASD and may be influenced by genetics. The value of MPAs for (early) detection should be further explored, as they might index individuals at increased risk for ASD in particular.

14.
Lakartidningen ; 1142017 Jun 02.
Artigo em Sueco | MEDLINE | ID: mdl-28586082

RESUMO

Sex chromosome abnormalities are among the most common genetic changes. The manifestations vary and may include growth abnormalities, specific appearance features, and other endocrinological and physical disorders, but also delayed psychomotor development, learning disabilities, and psychiatric conditions including ADHD and autism spectrum disorders. Increased knowledge about the relationship between sex chromosome abnormalities, development and psychiatric conditions would enable improved care of these patients.


Assuntos
Transtornos do Neurodesenvolvimento/genética , Aberrações dos Cromossomos Sexuais , Transtornos dos Cromossomos Sexuais/complicações , Adolescente , Criança , Proteínas de Homeodomínio/genética , Humanos , Transtornos dos Cromossomos Sexuais/epidemiologia , Proteína de Homoeobox de Baixa Estatura
15.
Nat Neurosci ; 20(8): 1043-1051, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28628100

RESUMO

Although de novo missense mutations have been predicted to account for more cases of autism than gene-truncating mutations, most research has focused on the latter. We identified the properties of de novo missense mutations in patients with neurodevelopmental disorders (NDDs) and highlight 35 genes with excess missense mutations. Additionally, 40 amino acid sites were recurrently mutated in 36 genes, and targeted sequencing of 20 sites in 17,688 patients with NDD identified 21 new patients with identical missense mutations. One recurrent site substitution (p.A636T) occurs in a glutamate receptor subunit, GRIA1. This same amino acid substitution in the homologous but distinct mouse glutamate receptor subunit Grid2 is associated with Lurcher ataxia. Phenotypic follow-up in five individuals with GRIA1 mutations shows evidence of specific learning disabilities and autism. Overall, we find significant clustering of de novo mutations in 200 genes, highlighting specific functional domains and synaptic candidate genes important in NDD pathology.


Assuntos
Sequência de Aminoácidos/genética , Transtorno Autístico/genética , Exoma/genética , Predisposição Genética para Doença , Mutação de Sentido Incorreto/genética , Feminino , Humanos , Masculino , Receptores de AMPA/genética , Receptores de Glutamato/genética
16.
Eur J Hum Genet ; 25(8): 946-951, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28513610

RESUMO

The introduction of whole-exome sequencing into the Pediatric Genetics clinic has increased the identification of novel genes associated with neurodevelopmental disorders and congenital anomalies. This agnostic approach has shed light on multiple proteins and pathways not previously known to be associated with disease. Here we report eight subjects from six families with predicted loss of function variants in ZNF462, a zinc-finger protein of unknown function. These individuals have overlapping phenotypes that include ptosis, metopic ridging, craniosynostosis, dysgenesis of the corpus callosum, and developmental delay. We propose that ZNF462 plays an important role in embryonic development, and is associated with craniofacial and neurodevelopmental abnormalities.


Assuntos
Agenesia do Corpo Caloso/genética , Blefaroptose/genética , Anormalidades Craniofaciais/genética , Proteínas de Ligação a DNA/genética , Deficiências do Desenvolvimento/genética , Haploinsuficiência , Proteínas do Tecido Nervoso/genética , Fatores de Transcrição/genética , Adulto , Agenesia do Corpo Caloso/diagnóstico , Blefaroptose/diagnóstico , Criança , Pré-Escolar , Anormalidades Craniofaciais/diagnóstico , Deficiências do Desenvolvimento/diagnóstico , Feminino , Humanos , Lactente , Masculino , Síndrome
17.
Am J Med Genet A ; 173(5): 1396-1399, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28319323

RESUMO

Singleton-Merten syndrome (MIM 182250) is an autosomal dominant inherited disorder characterized by early onset periodontitis, root resorption, osteopenia, osteoporosis, and aortic valve or thoracic aorta calcification. The disorder can have significant intrafamilial phenotypic variability. Here, we present a mother and daughter with Singleton-Merten syndrome harboring a previously described pathogenic missense mutation, c.2465G>A p.(Arg822Gln), in IFIH1 (interferon induced with helicase C domain 1), encoding MDA5 (Melanoma Differentiation-Associated protein 5). These data confirm the pathogenicity of IFIH1 c.2465G>A p.(Arg822Gln) for Singleton-Merten syndrome and affirm the striking phenotypic heterogeneity of this disorder. In addition, we expand the Singleton-Merten phenotype by adding severe systemic lupus erythematosus (SLE) to the clinical picture. Investigations of known SLE genes as well as a single nucleotide polymorphism suggested to be involved in development of SLE were normal.


Assuntos
Doenças da Aorta/genética , Hipoplasia do Esmalte Dentário/genética , Heterogeneidade Genética , Helicase IFIH1 Induzida por Interferon/genética , Metacarpo/anormalidades , Doenças Musculares/genética , Odontodisplasia/genética , Osteoporose/genética , Calcificação Vascular/genética , Adulto , Doenças da Aorta/fisiopatologia , Hipoplasia do Esmalte Dentário/fisiopatologia , Feminino , Humanos , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/fisiopatologia , Metacarpo/fisiopatologia , Doenças Musculares/fisiopatologia , Mutação de Sentido Incorreto , Odontodisplasia/fisiopatologia , Osteoporose/fisiopatologia , Fenótipo , Calcificação Vascular/fisiopatologia
18.
Nat Genet ; 49(4): 515-526, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28191889

RESUMO

Gene-disruptive mutations contribute to the biology of neurodevelopmental disorders (NDDs), but most of the related pathogenic genes are not known. We sequenced 208 candidate genes from >11,730 cases and >2,867 controls. We identified 91 genes, including 38 new NDD genes, with an excess of de novo mutations or private disruptive mutations in 5.7% of cases. Drosophila functional assays revealed a subset with increased involvement in NDDs. We identified 25 genes showing a bias for autism versus intellectual disability and highlighted a network associated with high-functioning autism (full-scale IQ >100). Clinical follow-up for NAA15, KMT5B, and ASH1L highlighted new syndromic and nonsyndromic forms of disease.


Assuntos
Transtorno Autístico/genética , Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Feminino , Humanos , Masculino , Mutação/genética , Fenótipo
19.
Otol Neurotol ; 38(1): 38-46, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27779564

RESUMO

OBJECTIVE: To evaluate if cochlear implantation is safe and constitutes an option for hearing rehabilitation of children with x-linked inner ear malformation. STUDY DESIGN: Retrospective patient review in combination with a multidisciplinary follow-up. SETTING: Tertiary referral hospital and cochlear implant program. PATIENTS: Ten children with severe-profound mixed hearing loss and radiological findings consistent with Incomplete Partition type 3 cochlear malformation received cochlear implants during the years 2007 to 2015. Nine of the children had a mutation affecting the gene POU3F4 on Xq21. INTERVENTION: Cochlear implantation. MAIN OUTCOME MEASURES: Surgical events, intraoperative measures and electrical stimulation levels, hearing and spoken language abilities. RESULTS: In all, 15 cochlear implantations were performed. In three cases the electrode was found to be in the internal auditory canal on intraoperative x-ray and repositioned successfully. One child had a postoperative rhinorrhea confirmed to be cerebrospinal fluid but this resolved on conservative treatment. No severe complications occurred. Postoperative electrical stimulation levels were higher in 9 of 10 children, as compared with typically reported average levels in patients with a normal cochlea. Eight patients developed spoken language to various degrees while two were still at precommunication level. However, speech recognition scores were lower than average pediatric cases. CONCLUSION: Cochlear implantation is a safe procedure for children with severe-profound mixed hearing loss related to POU3F4 mutation inner ear malformation. The children develop hearing and spoken language but outcome is below average for pediatric CI recipients.


Assuntos
Implante Coclear , Perda Auditiva Neurossensorial/congênito , Perda Auditiva Neurossensorial/cirurgia , Fatores do Domínio POU/genética , Criança , Pré-Escolar , Cromossomos Humanos X , Cóclea/cirurgia , Implante Coclear/efeitos adversos , Implante Coclear/métodos , Implantes Cocleares , Orelha Interna/anormalidades , Orelha Interna/cirurgia , Feminino , Doenças Genéticas Ligadas ao Cromossomo X , Perda Auditiva Neurossensorial/genética , Testes Auditivos , Humanos , Masculino , Mutação , Complicações Pós-Operatórias/epidemiologia , Estudos Retrospectivos , Resultado do Tratamento
20.
Hum Mutat ; 38(2): 180-192, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27862604

RESUMO

Most balanced translocations are thought to result mechanistically from nonhomologous end joining or, in rare cases of recurrent events, by nonallelic homologous recombination. Here, we use low-coverage mate pair whole-genome sequencing to fine map rearrangement breakpoint junctions in both phenotypically normal and affected translocation carriers. In total, 46 junctions from 22 carriers of balanced translocations were characterized. Genes were disrupted in 48% of the breakpoints; recessive genes in four normal carriers and known dominant intellectual disability genes in three affected carriers. Finally, seven candidate disease genes were disrupted in five carriers with neurocognitive disabilities (SVOPL, SUSD1, TOX, NCALD, SLC4A10) and one XX-male carrier with Tourette syndrome (LYPD6, GPC5). Breakpoint junction analyses revealed microhomology and small templated insertions in a substantive fraction of the analyzed translocations (17.4%; n = 4); an observation that was substantiated by reanalysis of 37 previously published translocation junctions. Microhomology associated with templated insertions is a characteristic seen in the breakpoint junctions of rearrangements mediated by error-prone replication-based repair mechanisms. Our data implicate that a mechanism involving template switching might contribute to the formation of at least 15% of the interchromosomal translocation events.


Assuntos
Mapeamento Cromossômico , Translocação Genética , Sequenciamento Completo do Genoma , Sequência de Bases , Quebra Cromossômica , Hibridização Genômica Comparativa , Variações do Número de Cópias de DNA , Feminino , Estudos de Associação Genética , Genômica/métodos , Genótipo , Recombinação Homóloga , Humanos , Hibridização in Situ Fluorescente , Cariótipo , Masculino , Fenótipo
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