Asunto(s)
Anomalías Múltiples , Anomalías del Ojo , Enfermedades Renales Quísticas , Humanos , Cerebelo/diagnóstico por imagen , Anomalías Múltiples/genética , Enfermedades Renales Quísticas/genética , Retina/diagnóstico por imagen , Anomalías del Ojo/diagnóstico , Anomalías del Ojo/genética , Monoéster Fosfórico Hidrolasas/genética , Monoéster Fosfórico Hidrolasas/metabolismo , Fenotipo , GenotipoRESUMEN
BACKGROUND: A neurodevelopmental syndrome was recently reported in four patients with SOX4 heterozygous missense variants in the high-mobility-group (HMG) DNA-binding domain. The present study aimed to consolidate clinical and genetic knowledge of this syndrome. METHODS: We newly identified 17 patients with SOX4 variants, predicted variant pathogenicity using in silico tests and in vitro functional assays and analysed the patients' phenotypes. RESULTS: All variants were novel, distinct and heterozygous. Seven HMG-domain missense and five stop-gain variants were classified as pathogenic or likely pathogenic variant (L/PV) as they precluded SOX4 transcriptional activity in vitro. Five HMG-domain and non-HMG-domain missense variants were classified as of uncertain significance (VUS) due to negative results from functional tests. When known, inheritance was de novo or from a mosaic unaffected or non-mosaic affected parent for patients with L/PV, and from a non-mosaic asymptomatic or affected parent for patients with VUS. All patients had neurodevelopmental, neurological and dysmorphic features, and at least one cardiovascular, ophthalmological, musculoskeletal or other somatic anomaly. Patients with L/PV were overall more affected than patients with VUS. They resembled patients with other neurodevelopmental diseases, including the SOX11-related and Coffin-Siris (CSS) syndromes, but lacked the most specific features of CSS. CONCLUSION: These findings consolidate evidence of a fairly non-specific neurodevelopmental syndrome due to SOX4 haploinsufficiency in neurogenesis and multiple other developmental processes.
Asunto(s)
Deformidades Congénitas de la Mano , Discapacidad Intelectual , Micrognatismo , Trastornos del Neurodesarrollo , Humanos , Micrognatismo/genética , Deformidades Congénitas de la Mano/genética , Discapacidad Intelectual/genética , Trastornos del Neurodesarrollo/genética , Síndrome , Fenotipo , ADN , Factores de Transcripción SOXC/genéticaRESUMEN
Pseudohypoaldosteronism type 1B is a rare autosomal recessive disorder caused by dysfunction of amiloride-sensitive epithelial sodium channels (ENaCs). We present the case of a neonate with cardiogenic shock after cardiac arrest due to profound hyperkalaemia. Genetic testing revealed a novel homozygous variant in SCNNIA We review diagnostic considerations including the molecular mechanisms of disease, discuss treatment approaches and highlight the possible significance of the diversity of pulmonary ENaCs.
Asunto(s)
Hiperpotasemia , Seudohipoaldosteronismo , Amilorida , Canales Epiteliales de Sodio/genética , Homocigoto , Humanos , Hiperpotasemia/diagnóstico , Hiperpotasemia/etiología , Recién Nacido , Seudohipoaldosteronismo/complicaciones , Seudohipoaldosteronismo/diagnóstico , Seudohipoaldosteronismo/genéticaRESUMEN
The semaphorin protein family is a diverse set of extracellular signaling proteins that perform fundamental roles in the development and operation of numerous biological systems, notably the nervous, musculoskeletal, cardiovascular, endocrine, and reproductive systems. Recently, recessive loss-of-function (LoF) variants in SEMA3A (semaphorin 3A) have been shown to result in a recognizable syndrome characterized by short stature, skeletal abnormalities, congenital heart defects, and variable additional anomalies. Here, we describe the clinical and molecular characterization of a female patient presenting with skeletal dysplasia, hypogonadotropic hypogonadism (HH), and anosmia who harbors a nonsense variant c.1633C>T (p.Arg555*) and a deletion of exons 15, 16, and 17 in SEMA3A in the compound heterozygous state. These variants were identified through next-generation sequencing analysis of a panel of 26 genes known to be associated with HH/Kallmann syndrome. Our findings further substantiate the notion that biallelic LoF SEMA3A variants cause a syndromic form of short stature and expand the phenotypic spectrum associated with this condition to include features of Kallmann syndrome.