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Ehlers–Danlos syndrome with lethal cardiac valvular dystrophy in males carrying a novel splice mutation in FLNA
Author(s) -
Ritelli Marco,
Morlino Silvia,
Giacopuzzi Edoardo,
Carini Giulia,
Cinquina Valeria,
Chiarelli Nicola,
Majore Silvia,
Colombi Marina,
Castori Marco
Publication year - 2017
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.38004
Subject(s) - filamin , genetics , flna , biology , dystrophy , joint hypermobility , exon , connective tissue disorder , splice site mutation , muscular dystrophy , missense mutation , mutation , medicine , pathology , alternative splicing , anatomy , gene , cytoskeleton , cell
Filamin A is an X‐linked, ubiquitous actin‐binding protein whose mutations are associated to multiple disorders with limited genotype–phenotype correlations. While gain‐of‐function mutations cause various bone dysplasias, loss‐of‐function variants are the most common cause of periventricular nodular heterotopias with variable soft connective tissue involvement, as well as X‐linked cardiac valvular dystrophy (XCVD). The term “Ehlers–Danlos syndrome (EDS) with periventricular heterotopias” has been used in females with neurological, cardiovascular, integument and joint manifestations, but this nosology is still a matter of debate. We report the clinical and molecular update of an Italian family with an X‐linked recessive soft connective tissue disorder and which was described, in 1975, as the first example of EDS type V of the Berlin nosology. The cutaneous phenotype of the index patient was close to classical EDS and all males died for a lethal cardiac valvular dystrophy. Whole exome sequencing identified the novel c.1829‐1G>C splice variation in FLNA in two affected cousins. The nucleotide change was predicted to abolish the canonical splice acceptor site of exon 13 and to activate a cryptic acceptor site 15 bp downstream, leading to in frame deletion of five amino acid residues (p.Phe611_Gly615del). The predicted in frame deletion clusters with all the mutations previously identified in XCVD and falls within the N‐terminus rod 1 domain of filamin A. Our findings expand the male‐specific phenotype of FLNA mutations that now includes classical‐like EDS with lethal cardiac valvular dystrophy, and offer further insights for the genotype–phenotype correlations within this spectrum. © 2016 Wiley Periodicals, Inc.