ABSTRACT
PURPOSE: Ciliopathies are highly heterogeneous clinical disorders of the primary cilium. We aim to characterize a large cohort of ciliopathies phenotypically and molecularly. METHODS: Detailed phenotypic and genomic analysis of patients with ciliopathies, and functional characterization of novel candidate genes. RESULTS: In this study, we describe 125 families with ciliopathies and show that deleterious variants in previously reported genes, including cryptic splicing variants, account for 87% of cases. Additionally, we further support a number of previously reported candidate genes (BBIP1, MAPKBP1, PDE6D, and WDPCP), and propose nine novel candidate genes (CCDC67, CCDC96, CCDC172, CEP295, FAM166B, LRRC34, TMEM17, TTC6, and TTC23), three of which (LRRC34, TTC6, and TTC23) are supported by functional assays that we performed on available patient-derived fibroblasts. From a phenotypic perspective, we expand the phenomenon of allelism that characterizes ciliopathies by describing novel associations including WDR19-related Stargardt disease and SCLT1- and CEP164-related Bardet-Biedl syndrome. CONCLUSION: In this cohort of phenotypically and molecularly characterized ciliopathies, we draw important lessons that inform the clinical management and the diagnostics of this class of disorders as well as their basic biology.
Subject(s)
Bardet-Biedl Syndrome , Ciliopathies , Alleles , Bardet-Biedl Syndrome/genetics , Cilia/genetics , Ciliopathies/genetics , Humans , Sodium ChannelsABSTRACT
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.
Subject(s)
Carrier Proteins/genetics , Hydrocephalus/genetics , Microtubule-Associated Proteins/genetics , Nerve Tissue Proteins/genetics , Child , Child, Preschool , Cohort Studies , Consanguinity , Exome , Female , Genes, Recessive , Humans , Hydrocephalus/pathology , Hydrocephalus/physiopathology , Infant , Male , Membrane Proteins , Mutation , Pedigree , Sequence Analysis, DNAABSTRACT
OBJECTIVE: To assess the postnatal outcome of fetuses with renal pelvis dilatation (RPD). METHODS: A retrospective study was conducted to review 61 fetuses found to have RPD by ultrasound (US) carried out from January 2008 to January 2012 at the Security Forces Hospital in Riyadh, Kingdom of Saudi Arabia. Five ended with intra uterine fetal death or early neonatal death, and were excluded. Of the remaining 56 cases, 22 cases were lost to follow up, and we were not able to contact them so were excluded. The remaining 34 cases were followed-up in our hospital, and their outcome were analyzed. The main outcome measures include: incidence of RPD diagnosed in our population, degree of hydronephrosis, postnatal diagnosis, and need for surgical intervention. Data on pregnancy and fetal outcome were collected from the files of the patients. RESULTS: Out of the 990 cases with sonographic abnormalities detected by antenatal US, the incidence of isolated RPD was 6.1%. Out of 34 cases, 15 patients had severe RPD (44% of cases), 41% of cases (14 patients) had moderate RPD, and 15% of cases (5 patients) had mild RPD, only 7 patients (21%) required surgery after delivery. CONCLUSION: The routine use of antenatal ultrasonography will lead to early diagnosis of urologic conditions that have postnatal consequences.
