RESUMO
Autosomal dominantly inherited mutations of BICD2 are associated with congenital-onset spinal muscular atrophy characterised by lower limb predominance. A few cases have also showed upper motor neuron pathology, including presenting with features resembling hereditary spastic paraplegia. The age-of-onset for the published families is usually at birth but also included cases with childhood- and adult-onset disease. In this report we described two isolated probands that presented in utero with features associated with reduced fetal movements. Both cases were diagnosed at birth with arthrogryposis multiplex congenita (AMC) and hypotonia. Other variable features included congenital fractures, hip dislocation, micrognathia, respiratory insufficiency, microcephaly and bilateral perisylvian polymicrogyria. Patient 1 is 4 years of age and stable, but shows significant motor developmental delay and delayed speech. Patient 2 passed away at 7 weeks of age. Through next generation sequencing we identified the same missense substitution in BICD2 (p.Arg694Cys) in both probands. Sanger sequencing showed that in both cases the mutation arose de novo. The in utero onset in both cases suggests that the p.Arg694Cys substitution may have a more deleterious effect on BICD2 function than previously described mutations. Our results broaden the phenotypes associated with BICD2 mutations to include AMC and cortical malformations and therefore to a similar phenotypic spectrum to that associated with its binding partner DYNC1H1.
Assuntos
Anormalidades Múltiplas/genética , Artrogripose/genética , Deficiência Intelectual/genética , Malformações do Desenvolvimento Cortical/genética , Proteínas Associadas aos Microtúbulos/genética , Mutação , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/terapia , Artrogripose/diagnóstico por imagem , Artrogripose/terapia , Pré-Escolar , Evolução Fatal , Humanos , Lactente , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/terapia , Masculino , Malformações do Desenvolvimento Cortical/diagnóstico por imagem , Malformações do Desenvolvimento Cortical/terapia , FenótipoRESUMO
BACKGROUND: Retrospective investigation of sudden unexplained death in the young (SUDY) reveals that a high proportion is due to inherited heart disease. OBJECTIVE: The purpose of this study was to ascertain the diagnostic value of postmortem long QT (LQT) genetic analysis in a prospective study of SUDY victims 1-40 years old. METHODS: Denaturing high-performance liquid chromatography or direct sequencing of LQT genes 1, 2, 3, 5, and 6 was performed, in a National New Zealand protocol, in SUDY victims aged 1-40 years. RESULTS: Over 26 months (2006-2008), DNA was stored at autopsy from 52 victims of sudden unexpected death. Further testing revealed a diagnosis in 19 cases (poisoning 4, dilated cardiomyopathy 3, myocarditis 3, other 9). The remaining 33 cases underwent genetic testing (age at death 18 months-40 years, median 25 years). Eighteen (55%) died during sleep or at rest, and 7 (21%) died during light activity. Rare missense variants in LQT genes were found in 5 (15%) cases (confidence interval 3%-27%): T96R in KCNQ1 (11-year-old male), P968L in KCNH2 (32-year-old female), P2006A in SCN5A (34-year-old female), and R67H and R98W in KCNE1 (17- and 38-year-old females, respectively). Evidence of pathogenicity was provided by in vitro evidence (T96R), family phenotype-genotype co-segregation (R98W, P2006A), and/or previous reports (R67H, P968L, P2006A, R98W). Family cardiac investigation was possible in 23 (70%) families and revealed probable cause of death for 5 (15%) other victims (confidence interval 3%-27%). CONCLUSION: Most community SUDY occurs at rest or during light activity. A diagnostic rate of 15% supports the transition of LQT genetic autopsy, combined with family investigation, into routine medical practice.
Assuntos
Morte Súbita Cardíaca/epidemiologia , Síndrome do QT Longo/genética , Canais de Potássio/genética , Canais de Sódio/genética , Adolescente , Adulto , Criança , Pré-Escolar , Cromatografia Líquida de Alta Pressão , Feminino , Testes Genéticos , Humanos , Lactente , Canal de Potássio KCNQ1/genética , Síndrome do QT Longo/epidemiologia , Masculino , Mutação de Sentido Incorreto , Canal de Sódio Disparado por Voltagem NAV1.5 , Nova Zelândia/epidemiologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana/genética , Estudos Prospectivos , Estudos Soroepidemiológicos , Adulto JovemRESUMO
We report on three male infants with de novo terminal deletions of chromosome 9q34.3. The clinical features are compared to the nine cases described in the literature. Case 1 and 3 were ascertained following the use of subtelomeric FISH to screen for a chromosomal anomaly, case 2 was confirmed by FISH probe following detection of a 9q deletion on standard karyotyping. Deletions in this region result in severe developmental delay, a distinct facial phenotype, cardiac anomalies, obesity, and respiratory failure, which may result in premature death. The delineation of the 9q deletion phenotype will aid diagnosis and genetic counseling as subtelomere FISH screening becomes more widely available.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 9/genética , Telômero/genética , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Bandeamento Cromossômico , Deficiências do Desenvolvimento/patologia , Face/anormalidades , Evolução Fatal , Cardiopatias Congênitas/patologia , Humanos , Hibridização in Situ Fluorescente , Lactente , Cariotipagem , Masculino , Insuficiência Respiratória/patologiaRESUMO
We describe the phenotypic features in a newborn infant with an unbalanced translocation 46,XY, der(22) inv(4) (p14p16.1) t(4;22) (p15.1;q13.31)pat. The phenotype was consistent with partial trisomy 4p syndrome. Severe bilateral hydronephrosis was diagnosed at a 31 week prenatal ultrasound scan. Both the patient phenotype and the partial trisomy are unusual, the latter due to the complex nature of the chromosomal rearrangement.
