Congenital hydrocephalus: new Mendelian mutations and evidence for oligogenic inheritance.

BACKGROUND: Congenital hydrocephalus is characterized by ventriculomegaly, defined as a dilatation of cerebral ventricles, and thought to be due to impaired cerebrospinal fluid (CSF) homeostasis. Primary congenital hydrocephalus is a subset of cases with prenatal onset and absence of another primary cause, e.g., brain hemorrhage. Published series report a Mendelian cause in only a minority of cases. In this study, we analyzed exome data of PCH patients in search of novel causal genes and addressed the possibility of an underlying oligogenic mode of inheritance for PCH. MATERIALS AND METHODS: We sequenced the exome in 28 unrelated probands with PCH, 12 of whom from families with at least two affected siblings and 9 of whom consanguineous, thereby increasing the contribution of genetic causes. Patient exome data were first analyzed for rare (MAF < 0.005) transmitted or de novo variants. Population stratification of unrelated PCH patients and controls was determined by principle component analysis, and outliers identified using Mahalanobis distance 5% as cutoff. Patient and control exome data for genes biologically related to cilia (SYScilia database) were analyzed by mutation burden test. RESULTS: In 18% of probands, we identify a causal (pathogenic or likely pathogenic) variant of a known hydrocephalus gene, including genes for postnatal, syndromic hydrocephalus, not previously reported in isolated PCH. In a further 11%, we identify mutations in novel candidate genes. Through mutation burden tests, we demonstrate a significant burden of genetic variants in genes coding for proteins of the primary cilium in PCH patients compared to controls. CONCLUSION: Our study confirms the low contribution of Mendelian mutations in PCH and reports PCH as a phenotypic presentation of some known genes known for syndromic, postnatal hydrocephalus. Furthermore, this study identifies novel Mendelian candidate genes, and provides evidence for oligogenic inheritance implicating primary cilia in PCH.

High frequency of sex chromosomal disomy in spermatozoa of Lebanese infertile men.

In Lebanon, assisted reproductive techniques (ART) are widely used to overcome infertility, but the genetic risk associated with these techniques is still ignored. In this study, in order to estimate the transmission risk of paternal chromosomal anomalies to ART offspring, the meiotic segregation of chromosomes X, Y, 18, and 21 was analyzed by fluorescent in situ hybridization on the spermatozoa of 19 Lebanese infertile men. Our results show significantly higher frequencies of sex chromosome disomies in the group of patients with oligozoospermia compared with a control group of fertile males. Interestingly, the sex chromosome aneuploidy rates were highly variable between oligozoospermic patients, and ranged between 0.9% and 12.87%. No significant increase in aneuploidy rates was found for the group of nonoligozoospermic patients with asthenozoospermia and/or teratozoospermia. In addition, the disomy rate for chromosome 21 was analyzed in 8 patients, in whom higher disomy rates were shown as compared with the controls. Altogether, the results suggest that Lebanese oligozoospermic men undergoing ART may have an increased risk of transmitting sex chromosome anomalies to their offspring, as well as, in some cases, trisomy 21. Based on this work, genetic counseling programs for Lebanese infertile couples undergoing ART procedures should be developed, in order to improve the investigation and selection of Lebanese infertile couple candidates for ART procedures and optimize the choice of ART techniques.