RESUMEN
OBJECTIVE: Congenital hydrocephalus is an important birth defect, the genetics of which remains incompletely understood. To date, only 4 genes are known to cause Mendelian diseases in which congenital hydrocephalus is the main or sole clinical feature, 2 X-linked (L1CAM and AP1S2) and 2 autosomal recessive (CCDC88C and MPDZ). In this study, we aimed to determine the genetic etiology of familial congenital hydrocephalus with the assumption that these cases represent Mendelian forms of the disease. METHODS: Exome sequencing combined, where applicable, with positional mapping. RESULTS: We identified a likely causal mutation in the majority of these families (21 of 27, 78%), spanning 16 genes, none of which is X-linked. Ciliopathies and dystroglycanopathies were the most common etiologies of congenital hydrocephalus in our cohort (19% and 26%, respectively). In 1 family with 4 affected members, we identified a homozygous truncating variant in EML1, which we propose as a novel cause of congenital hydrocephalus in addition to its suggested role in cortical malformation. Similarly, we show that recessive mutations in WDR81, previously linked to cerebellar ataxia, mental retardation, and disequilibrium syndrome 2, cause severe congenital hydrocephalus. Furthermore, we confirm the previously reported candidacy of MPDZ by presenting a phenotypic spectrum of congenital hydrocephalus associated with 5 recessive alleles. INTERPRETATION: Our study highlights the importance of recessive mutations in familial congenital hydrocephalus and expands the locus heterogeneity of this condition. Ann Neurol 2017;81:890-897.
Asunto(s)
Proteínas Portadoras/genética , Hidrocefalia/genética , Proteínas Asociadas a Microtúbulos/genética , Proteínas del Tejido Nervioso/genética , Niño , Preescolar , Estudios de Cohortes , Consanguinidad , Exoma , Femenino , Genes Recesivos , Humanos , Hidrocefalia/patología , Hidrocefalia/fisiopatología , Lactante , Masculino , Proteínas de la Membrana , Mutación , Linaje , Análisis de Secuencia de ADNRESUMEN
Spondylocostal dysotosis (SCD) is a rare developmental congenital abnormality of the axial skeleton. Mutation of genes in the Notch signaling pathway cause SCD types 1-5. Dextrocardia with situs inversus is a rare congenital malformation in which the thoracic and abdominal organs are mirror images of normal. Such laterality defects are associated with gene mutations in the Nodal signaling pathway or cilia assembly or function. We investigated two distantly related individuals with a rare combination of severe segmental defects of the vertebrae (SDV) and dextrocardia with situs inversus. We found that both individuals were homozygous for the same mutation in HES7, and that this mutation caused a significant reduction of HES7 protein function; HES7 mutation causes SCD4. Two other individuals with SDV from two unrelated families were found to be homozygous for the same mutation. Interestingly, although the penetrance of the vertebral defects was complete, only 3/7 had dextrocardia with situs inversus, suggesting randomization of left-right patterning. Two of the affected individuals presented with neural tube malformations including myelomeningocele, spina bifida occulta and/or Chiari II malformation. Such neural tube phenotypes are shared with the originally identified SCD4 patient, but have not been reported in the other forms of SCD. In conclusion, it appears that mutation of HES7 is uniquely associated with defects in vertebral, heart and neural tube formation, and this observation will help provide a discriminatory diagnostic guide in patients with SCD, as well as inform molecular genetic testing.
Asunto(s)
Anomalías Múltiples/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Dextrocardia/genética , Cardiopatías Congénitas/genética , Hernia Diafragmática/genética , Mutación , Situs Inversus/genética , Anomalías Múltiples/diagnóstico , Sustitución de Aminoácidos , Animales , Mapeo Cromosómico , Hibridación Genómica Comparativa , Consanguinidad , Dextrocardia/diagnóstico , Femenino , Genotipo , Cardiopatías Congénitas/diagnóstico , Hernia Diafragmática/diagnóstico , Humanos , Lactante , Recién Nacido , Masculino , Ratones , Linaje , Fenotipo , Situs Inversus/diagnósticoAsunto(s)
Receptores de Activinas Tipo II/genética , Malformaciones Arteriovenosas/genética , Hepatopatías/genética , Telangiectasia Hemorrágica Hereditaria/diagnóstico , Femenino , Humanos , Recién Nacido , Hepatopatías/congénito , Masculino , Embarazo , Telangiectasia Hemorrágica Hereditaria/genética , Ultrasonografía PrenatalRESUMEN
AIM: Infantile scimitar syndrome is a rare condition, with most of the literature reports being limited to case reports and a few case series. The aim of this study was to review patients with infantile scimitar syndrome who presented to our hospital from July 2000 to January 2011. MATERIALS AND METHODS: In this retrospective study, we evaluated the medical records of patients aged 0-14 years who were symptomatic before the age of 1 year and were subsequently diagnosed with the syndrome. A total of 16 patients with the infantile form of scimitar syndrome were identified from the database. RESULTS: The median age at presentation was 14 days, with a median age at diagnosis of 55 days. Fifty-six percent of the patients were females. Tachypnea was the major presenting symptom and 13 out of 16 patients had pulmonary hypertension. Of the 13 patients with pulmonary hypertension, 7 had systemic collaterals, which were treated by coil occlusion together with medications, and 3 had corrective surgery. The mortality rate was 3/16 (18.8%) over the 10.5 years study period. CONCLUSIONS: Infantile scimitar syndrome is a rare congenital anomaly that needs a high degree of suspicion for early referral and management. The association of the syndrome with pulmonary hypertension leads to recurrent and prolonged hospitalization.