Compound heterozygous variants in the multiple PDZ domain protein (MPDZ) cause a case of mild non-progressive communicating hydrocephalus

Nesreen K Al-Jezawi,Lihadh Al-Gazali,Bassam R Ali,Aisha M Al-Shamsi,Salma Ben-Salem,Anne John,Ranjit Vijayan,Jehan Suleiman

doi:10.1186/s12881-018-0540-x

Nesreen K Al-Jezawi, Lihadh Al-Gazali + Show 6 more

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https://doi.org/10.1186/s12881-018-0540-x

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Abstract

BackgroundCongenital hydrocephalus (CH) results from the accumulation of excessive amounts of cerebrospinal fluid (CSF) in the brain, often leading to severe neurological impairments. However, the adverse effects of CH can be reduced if the condition is detected and treated early. Earlier reports demonstrated that some CH cases are caused by mutations in L1CAM gene encoding the neural cell adhesion molecule L1. On the other hand, recent studies have implicated the multiple PDZ domain (MPDZ) gene in some severe forms of CH, inherited in an autosomal recessive pattern.MethodsIn this study, whole-exome and Sanger sequencing were performed on a 9 months old Emirati child clinically diagnosed by CH. In addition, in silico, cellular, and molecular assays have been conducted to confirm pathogenicity of the identified variants and to establish disease mechanism.ResultsWhole exome sequencing revealed two compound heterozygous novel variants (c.394G > A and c.1744C > G) in the affected child within the MPDZ gene. Segregation analysis revealed that each of the parents is heterozygous for one of the two variants and therefore passed that variant to their child. The outcome of the in silico and bioinformatics analyses came in line with the experimental data, suggesting that the two variants are most likely disease causing.ConclusionsThe compound heterozygous variants identified in this study are the most likely cause of CH in the affected child. The study further confirms MPDZ as a gene underlying some CH cases.

Highlights

Congenital hydrocephalus (CH) results from the accumulation of excessive amounts of cerebrospinal fluid (CSF) in the brain, often leading to severe neurological impairments
Al-Jezawi et al BMC Medical Genetics (2018) 19:34. Another gene associated with hydrocephalus is the AP1S2 which encodes a subunit of the adaptor protein 1 [11]
multiple PDZ domain (MPDZ) proteins are made of multiple domains that can bind multivalent scaffold proteins, and regulate intracellular signaling, receptor clustering and polarity of epithelial cells [17]. We report in this manuscript an Emirati family with a child affected by congenital non-progressive communicating hydrocephalus, who was found to be compound heterozygous for two novel likely pathogenic variants in the MPDZ gene

Summary

Introduction

Congenital hydrocephalus (CH) results from the accumulation of excessive amounts of cerebrospinal fluid (CSF) in the brain, often leading to severe neurological impairments. Earlier reports demonstrated that some CH cases are caused by mutations in L1CAM gene encoding the neural cell adhesion molecule L1. Recent studies have implicated the multiple PDZ domain (MPDZ) gene in some severe forms of CH, inherited in an autosomal recessive pattern. Al-Jezawi et al BMC Medical Genetics (2018) 19:34 Another gene associated with hydrocephalus is the AP1S2 which encodes a subunit of the adaptor protein 1 [11]. Al-Dosari et al, have recently reported cases from two Saudi families with congenital hydrocephalus and identified a founder homozygous mutation in MPDZ gene leading to a truncated protein. The hydrocephalus in the two families was very severe leading to stillbirths in two of the affected cases, and death of several affected children in early infancy [12]. Histological and confocal studies performed on post-mortem sections revealed multifocal ependymal rosette formation and absence of MPDZ in ependymal lining [13]

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