RESUMEN
OBJECTIVE: Exome sequencing is a successful option for diagnosing individuals with previously uncharacterized genetic conditions, however little has been reported regarding its utility in a prenatal setting. The goal of this study is to describe the results from a cohort of fetuses for which exome sequencing was performed. METHODS: We performed a retrospective analysis of the first seven cases referred to our laboratory for exome sequencing following fetal demise or termination of pregnancy. All seven pregnancies had multiple congenital anomalies identified by level II ultrasound. Exome sequencing was performed on trios using cultured amniocytes or products of conception from the affected fetuses. RESULTS: Relevant alterations were identified in more than half of the cases (4/7). Three of the four were categorized as 'positive' results, and one of the four was categorized as a 'likely positive' result. The provided diagnoses included osteogenesis imperfecta II (COL1A2), glycogen storage disease IV (GBE1), oral-facial-digital syndrome 1 (OFD1), and RAPSN-associated fetal akinesia deformation sequence. CONCLUSION: This data suggests that exome sequencing is likely to be a valuable diagnostic testing option for pregnancies with multiple congenital anomalies detected by prenatal ultrasound; however, additional studies with larger cohorts of affected pregnancies are necessary to confirm these findings.
Asunto(s)
Anomalías Múltiples/genética , Anomalías Congénitas/genética , Exoma/genética , Osteogénesis Imperfecta/genética , Anomalías Múltiples/diagnóstico por imagen , Aborto Inducido , Artrogriposis/diagnóstico por imagen , Artrogriposis/genética , Colágeno Tipo I/genética , Anomalías Congénitas/diagnóstico por imagen , Femenino , Muerte Fetal , Pruebas Genéticas , Sistema de la Enzima Desramificadora del Glucógeno/genética , Enfermedad del Almacenamiento de Glucógeno Tipo IV/diagnóstico por imagen , Enfermedad del Almacenamiento de Glucógeno Tipo IV/genética , Humanos , Masculino , Mutación , Síndromes Orofaciodigitales/diagnóstico por imagen , Síndromes Orofaciodigitales/genética , Osteogénesis Imperfecta/diagnóstico por imagen , Embarazo , Proteínas/genética , Estudios Retrospectivos , Análisis de Secuencia de ADN , Ultrasonografía PrenatalRESUMEN
The Na+/K+- ATPase acts as an ion pump maintaining the essential plasma membrane potential in all mammalian cell types, and is essential for many cellular functions. There are four α isoforms (α1, α2, α3 and α4) with distinct expression patterns, kinetic properties and substrate affinity. The α2-isoform is encoded by ATP1A2 and evidence supports its utmost importance in Cl- homeostasis in neurons, and in the function of respiratory neurons at birth. Monallelic pathogenic variants in ATP1A2 are associated with familial hemiplegic migraine type 2 (FHM2) and on rare occasions with alternating hemiplegia of childhood 1 (AHC1). To date, no instances of biallelic loss of function variants have been reported in humans. However, Atp1a2 homozygous loss of function knockout mice (α2-/- mice) show severe motor deficits, with lack of spontaneous movements, and are perinatally lethal due to absent respiratory activity. In this report we describe three newborns from two unrelated families, who died neonatally, presenting in utero with an unusual form of fetal hydrops, seizures and polyhydramnios. At birth they had multiple joint contractures (e.g. arthrogryposis), microcephaly, malformations of cortical development, dysmorphic features and severe respiratory insufficiency. Biallelic loss of function variants in ATP1A2, predicted to be pathogenic were found on whole exome sequencing. We propose that this is a distinctive new syndrome caused by complete absence of Na+/K+- ATPase α2-isoform expression.