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Ann Neurol. 2017 Jun;81(6):890-897. doi: 10.1002/ana.24964.

The genetic landscape of familial congenital hydrocephalus.

Author information

1
Departments of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
2
Department of Obstetrics and Gynecology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
3
Department of Surgery, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
4
Department of Medical Genetics, King Fahad General Hospital, Jeddah, Saudi Arabia.
5
Department of Pediatrics, Security Forces Hospital, Riyadh, Saudi Arabia.
6
Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
7
Maternal Fetal Medicine Department, Women's Specialized Hospital, King Fahad Medical City, Riyadh, Saudi Arabia.
8
Bnoon Medical Center, Riyadh, Saudi Arabia.
9
Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
10
Division of Clinical and Metabolic Genetics and, Department of Paediatrics, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
11
Neurology, Department of Paediatrics, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
12
Department of Pediatric Subspecialties, Children's Hospital, King Fahad Medical City, Riyadh, Saudi Arabia.
13
Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
14
Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.

Abstract

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.

PMID:
28556411
DOI:
10.1002/ana.24964
[Indexed for MEDLINE]

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