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Hum Mutat ; 38(11): 1477-1484, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28726266


Biallelic GLDN mutations have recently been identified among infants with lethal congenital contracture syndrome 11 (LCCS11). GLDN encodes gliomedin, a protein required for the formation of the nodes of Ranvier and development of the human peripheral nervous system. We report six infants and children from four unrelated families with biallelic GLDN mutations, four of whom survived beyond the neonatal period into infancy, childhood, and late adolescence with intensive care and chronic respiratory and nutritional support. Our findings expand the genotypic and phenotypic spectrum of LCCS11 and demonstrate that the condition may not necessarily be lethal in the neonatal period.

Artrogripose/diagnóstico , Artrogripose/genética , Genes Letais , Proteínas de Membrana/genética , Mutação , Proteínas do Tecido Nervoso/genética , Fenótipo , Artrogripose/mortalidade , Biópsia , Análise Mutacional de DNA , Evolução Fatal , Estudos de Associação Genética , Humanos , Lactente , Recém-Nascido , Masculino , Linhagem , Raízes Nervosas Espinhais/ultraestrutura , Sequenciamento Completo do Exoma
Genet Med ; 18(11): 1111-1118, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-26963284


BACKGROUND: Chromosome 15q13.3 represents a hotspot for genomic rearrangements due to repetitive sequences mediating nonallelic homologous recombination. Deletions of 15q13.3 have been identified in the context of multiple neurological and psychiatric disorders, but a prospective clinical and behavioral assessment of affected individuals has not yet been reported. METHODS: Eighteen subjects with 15q13.3 microdeletion underwent a series of behavioral assessments, along with clinical history and physical examination, to comprehensively define their behavioral phenotypes. RESULTS: Cognitive deficits are the most prevalent feature in 15q13.3 deletion syndrome, with an average nonverbal IQ of 60 among the patients studied. Autism spectrum disorder was highly penetrant, with 31% of patients meeting clinical criteria and exceeding cutoff scores on both ADOS-2 and ADI-R. Affected individuals exhibited a complex pattern of behavioral abnormalities, most notably hyperactivity, attention problems, withdrawal, and externalizing symptoms, as well as impairments in functional communication, leadership, adaptive skills, and activities of daily living. CONCLUSIONS: The 15q13.3 deletion syndrome encompasses a heterogeneous behavioral phenotype that poses a major challenge to parents, caregivers, and treating providers. Further work to more clearly delineate genotype-phenotype relationships in 15q13.3 deletions will be important for anticipatory guidance and development of targeted therapies.Genet Med 18 11, 1111-1118.

Transtorno do Espectro Autista/genética , Transtornos Cromossômicos/genética , Disfunção Cognitiva/genética , Deficiência Intelectual/genética , Convulsões/genética , Atividades Cotidianas , Adolescente , Adulto , Transtorno do Espectro Autista/fisiopatologia , Criança , Deleção Cromossômica , Transtornos Cromossômicos/fisiopatologia , Cromossomos Humanos Par 15/genética , Disfunção Cognitiva/fisiopatologia , Feminino , Estudos de Associação Genética , Humanos , Deficiência Intelectual/fisiopatologia , Masculino , Linhagem , Convulsões/fisiopatologia
Am J Med Genet A ; 152A(8): 1951-9, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20635359


Monosomy 1p36 is the most common terminal deletion syndrome seen in humans, occurring in approximately 1 in 5,000 live births. Common features include mental retardation, characteristic dysmorphic features, hypotonia, seizures, hearing loss, heart defects, cardiomyopathy, and behavior abnormalities. Similar phenotypes are seen among patients with a variety of deletion sizes, including terminal and interstitial deletions, complex rearrangements, and unbalanced translocations. Consequently, critical regions harboring causative genes for each of these features have been difficult to identify. Here we report on five individuals with 200-823 kb overlapping deletions of proximal 1p36.33, four of which are apparently de novo. They present with features of monosomy 1p36, including developmental delay and mental retardation, dysmorphic features, hypotonia, behavioral abnormalities including hyperphagia, and seizures. The smallest region of deletion overlap is 174 kb and contains five genes; these genes are likely candidates for some of the phenotypic features in monosomy 1p36. Other genes deleted in a subset of the patients likely play a contributory role in the phenotypes, including GABRD and seizures, PRKCZ and neurologic features, and SKI and dysmorphic and neurologic features. Characterization of small deletions is important for narrowing critical intervals and for the identification of causative or candidate genes for features of monosomy 1p36 syndrome.

Anormalidades Múltiplas , Deleção Cromossômica , Cromossomos Humanos Par 1/genética , Monossomia , Adolescente , Adulto , Pré-Escolar , Proteínas de Ligação a DNA/genética , Deficiências do Desenvolvimento/genética , Feminino , Humanos , Hibridização in Situ Fluorescente , Masculino , Doenças do Sistema Nervoso/genética , Fenótipo , Proteína Quinase C/genética , Proteínas Proto-Oncogênicas/genética , Receptores de GABA-A/genética , Convulsões/genética , Síndrome , Adulto Jovem
Am J Hum Genet ; 82(1): 199-207, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18179900


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.

Transtorno Autístico/genética , Predisposição Genética para Doença , Glicoproteínas/genética , Neuropeptídeos/genética , Aberrações Cromossômicas , Cromossomos Humanos Par 2 , Glicoproteínas/química , Humanos , Mutação de Sentido Incorreto , Neuropeptídeos/química , Estrutura Terciária de Proteína , Análise de Sequência de DNA