Prune belly syndrome in surviving males can be caused by Hemizygous missense mutations in the X-linked Filamin A gene

Nida S Iqbal,Catherine Chen,Angelena B Edwards,Adam J Kern,Linda A Baker,Steven M Harrison,Luke T Smith,Thomas A Jascur,Chao Xing,Shaohua Zhang,Erin S Choi,Emma J Sanchez,Michelle K Arevalo,Angela E Scheuerle

doi:10.1186/s12881-020-0973-x

Nida S Iqbal, Catherine Chen + Show 12 more

Open Access

https://doi.org/10.1186/s12881-020-0973-x

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Abstract

BackgroundPrune belly syndrome (PBS) is a rare, multi-system congenital myopathy primarily affecting males that is poorly described genetically. Phenotypically, its morbidity spans from mild to lethal, however, all isolated PBS cases manifest three cardinal pathological features: 1) wrinkled flaccid ventral abdominal wall with skeletal muscle deficiency, 2) urinary tract dilation with poorly contractile smooth muscle, and 3) intra-abdominal undescended testes. Despite evidence for a genetic basis, previously reported PBS autosomal candidate genes only account for one consanguineous family and single cases.MethodsWe performed whole exome sequencing (WES) of two maternal adult half-brothers with syndromic PBS (PBS + Otopalatodigital spectrum disorder [OPDSD]) and two unrelated sporadic individuals with isolated PBS and further functionally validated the identified mutations.ResultsWe identified three unreported hemizygous missense point mutations in the X-chromosome gene Filamin A (FLNA) (c.4952 C > T (p.A1448V), c.6727C > T (p.C2160R), c.5966 G > A (p.G2236E)) in two related cases and two unrelated sporadic individuals. Two of the three PBS mutations map to the highly regulatory, stretch-sensing Ig19–21 region of FLNA and enhance binding to intracellular tails of the transmembrane receptor β-integrin 1 (ITGβ1).ConclusionsFLNA is a regulatory actin-crosslinking protein that functions in smooth muscle cells as a mechanosensing molecular scaffold, transmitting force signals from the actin-myosin motor units and cytoskeleton via binding partners to the extracellular matrix. This is the first evidence for an X-linked cause of PBS in multiple unrelated individuals and expands the phenotypic spectrum associated with FLNA in males surviving even into adulthood.

Highlights

Prune belly syndrome (PBS) is a rare, multi-system congenital myopathy primarily affecting males that is poorly described genetically
A true urethral obstruction is observed in only 10–20% of Prune Belly Syndrome (PBS) autopsy cases and does not account for situations where significant abdominal muscular hypoplasia is observed with only a mild urogenital defect [9]
Variant call files were filtered to exclude those with a minor allele frequency (MAF) too high to account for PBS from public databases including, ExAC, gnomAD, 1000 genomes, (ExAC AF < 0.005 for homozygous variants and ExAC AF < 0.00005 for heterozygous or hemizygous variants) and only functional variants were included for further analysis

Summary

Introduction

Prune belly syndrome (PBS) is a rare, multi-system congenital myopathy primarily affecting males that is poorly described genetically. Despite evidence for a genetic basis, previously reported PBS autosomal candidate genes only account for one consanguineous family and single cases. The classic triad defining PBS, which almost exclusively affects males, includes 1) the wrinkled, prune-like ventral abdominal skin with underlying flaccid hypoplastic skeletal muscle, 2) urinary tract dilation including megacystis and megaureter. Five autosomal genes, including CHRM3, HNF1β, ACTA2, ACTG2 and STIM1, have been reported with potentially causal DNA variants, including structural, copy number, and single nucleotide variants, these genes each only account for one or two PBS cases or one PBS multiplex consanguineous kindred [32,33,34,35,36,37,38]. None of the currently suggested candidate genes fit an X-linked recessive mode of inheritance and functional data is lacking for many of these candidate genetic variants

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