Abstract
Terminal osseous dysplasia with pigmentary defects (TODPD), also known as digitocutaneous dysplasia, is one of the X‐linked filaminopathies caused by a variety of
FLNA
‐variants. TODPD is characterized by skeletal defects, skin fibromata and dysmorphic facial features. So far, only a single recurrent variant (c.5217G>A;p.Val1724_Thr1739del) in
FLNA
has found to be responsible for TODPD. We identified a novel c.5217+5G>C variant in
FLNA
in a female proband with skeletal defects, skin fibromata, interstitial lung disease, epilepsy, and restrictive cardiomyopathy. This variant causes mis‐splicing of exon 31 predicting the production of a FLNA‐protein with an in‐frame‐deletion of 16 residues identical to the miss‐splicing‐effect of the recurrent TODPD c.5217G>A variant. This mis‐spliced transcript was explicitly detected in heart tissue, but was absent from blood, skin, and lung. X‐inactivation analyses showed extreme skewing with almost complete inactivation of the mutated allele (>90%) in these tissues, except for heart. The mother of the proband, who also has fibromata and skeletal abnormalities, is also carrier of the
FLNA
‐variant and was diagnosed with noncompaction cardiomyopathy after cardiac screening. No other relevant variants in cardiomyopathy‐related genes were found. Here we describe a novel variant in
FLNA
(c.5217+5G>C) as the second pathogenic variant responsible for TODPD. Cardiomyopathy has not been described as a phenotypic feature of TODPD before.