RESUMO
PURPOSE: Neonatal patients are particularly appropriate for utilization of diagnostic exome sequencing (DES), as many Mendelian diseases are known to present in this period of life but often with complex, heterogeneous features. We attempted to determine the diagnostic rates and features of neonatal patients undergoing DES. METHODS: The clinical histories and results of 66 neonatal patients undergoing DES were retrospectively reviewed. RESULTS: Clinical DES identified potentially relevant findings in 25 patients (37.9%). The majority of patients had structural anomalies such as birth defects, dysmorphic features, cardiac, craniofacial, and skeletal defects. The average time for clinical rapid testing was 8 days. CONCLUSION: Our observations demonstrate the utility of family-based exome sequencing in neonatal patients, including familial cosegregation analysis and comprehensive medical review.
Assuntos
Sequenciamento do Exoma/métodos , Exoma/genética , Doenças Genéticas Inatas/diagnóstico , Patologia Molecular/métodos , Feminino , Doenças Genéticas Inatas/genética , Humanos , Recém-Nascido , Masculino , Mutação , Estudos Retrospectivos , Análise de Sequência de DNARESUMO
A range of phenotypes including Greig cephalopolysyndactyly and Pallister-Hall syndromes (GCPS, PHS) are caused by pathogenic mutation of the GLI3 gene. To characterize the clinical variability of GLI3 mutations, we present a subset of a cohort of 174 probands referred for GLI3 analysis. Eighty-one probands with typical GCPS or PHS were previously reported, and we report the remaining 93 probands here. This includes 19 probands (12 mutations) who fulfilled clinical criteria for GCPS or PHS, 48 probands (16 mutations) with features of GCPS or PHS but who did not meet the clinical criteria (sub-GCPS and sub-PHS), 21 probands (6 mutations) with features of PHS or GCPS and oral-facial-digital syndrome, and 5 probands (1 mutation) with nonsyndromic polydactyly. These data support previously identified genotype-phenotype correlations and demonstrate a more variable degree of severity than previously recognized. The finding of GLI3 mutations in patients with features of oral-facial-digital syndrome supports the observation that GLI3 interacts with cilia. We conclude that the phenotypic spectrum of GLI3 mutations is broader than that encompassed by the clinical diagnostic criteria, but the genotype-phenotype correlation persists. Individuals with features of either GCPS or PHS should be screened for mutations in GLI3 even if they do not fulfill clinical criteria.
Assuntos
Anormalidades Múltiplas/genética , Fatores de Transcrição Kruppel-Like/genética , Mutação , Proteínas do Tecido Nervoso/genética , Síndrome de Pallister-Hall/patologia , Polidactilia/patologia , Sindactilia/patologia , Anormalidades Craniofaciais/genética , Genótipo , Humanos , Anormalidades da Boca/genética , Síndrome de Pallister-Hall/genética , Fenótipo , Polidactilia/genética , Sindactilia/genética , Proteína Gli3 com Dedos de ZincoRESUMO
Hypotonia-cystinuria syndrome (HCS) is a recessive disorder caused by microdeletions of SLC3A1 and PREPL on chromosome 2p21. Patients present with generalized hypotonia at birth, failure to thrive, growth retardation and cystinuria type I. While the initially described HCS families live in small regions in Belgium and France, we have now identified HCS alleles in patients and carriers from the Netherlands, Italy, Canada and United States of America. Surprisingly, among the nine deletions detected in those patients, only one novel deletion was found. Furthermore, one previously described deletion was found six times, another twice. Finally, we have investigated the frequency of both deletions using a random Belgian cohort. Given the global occurrence, HCS should be considered in the differential diagnosis of neonatal hypotonia.
Assuntos
Deleção Cromossômica , Cistinúria/genética , Hipotonia Muscular/genética , Sistemas de Transporte de Aminoácidos Básicos/genética , Sistemas de Transporte de Aminoácidos Neutros/genética , Cromossomos Humanos Par 2/genética , Primers do DNA/genética , Genes Recessivos , Genética Populacional , Haplótipos , Homozigoto , Humanos , Recém-Nascido , Hipotonia Muscular/congênito , Fenótipo , Reação em Cadeia da Polimerase , Prolil Oligopeptidases , Serina Endopeptidases/genética , SíndromeRESUMO
Mutations in the GLI3 zinc-finger transcription factor gene cause Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS), which are variable but distinct clinical entities. We hypothesized that GLI3 mutations that predict a truncated functional repressor protein cause PHS and that functional haploinsufficiency of GLI3 causes GCPS. To test these hypotheses, we screened patients with PHS and GCPS for GLI3 mutations. The patient group consisted of 135 individuals: 89 patients with GCPS and 46 patients with PHS. We detected 47 pathological mutations (among 60 probands); when these were combined with previously published mutations, two genotype-phenotype correlations were evident. First, GCPS was caused by many types of alterations, including translocations, large deletions, exonic deletions and duplications, small in-frame deletions, and missense, frameshift/nonsense, and splicing mutations. In contrast, PHS was caused only by frameshift/nonsense and splicing mutations. Second, among the frameshift/nonsense mutations, there was a clear genotype-phenotype correlation. Mutations in the first third of the gene (from open reading frame [ORF] nucleotides [nt] 1-1997) caused GCPS, and mutations in the second third of the gene (from ORF nt 1998-3481) caused primarily PHS. Surprisingly, there were 12 mutations in patients with GCPS in the 3' third of the gene (after ORF nt 3481), and no patients with PHS had mutations in this region. These results demonstrate a robust correlation of genotype and phenotype for GLI3 mutations and strongly support the hypothesis that these two allelic disorders have distinct modes of pathogenesis.