Terminal osseous dysplasia with pigmentary defects and cardiomyopathy caused by a novel FLNA variant

Lynne Rumping, Marja W Wessels, Alex V Postma, Joost van Schuppen, Marjon A van Slegtenhorst, Jasper J Saris, J Peter van Tintelen, Stephen P Robertson, Mariëlle Alders, Saskia M Maas, Ronald H Lekanne Deprez

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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.

Original languageEnglish
Pages (from-to)3814-3820
Number of pages7
JournalAmerican Journal of Medical Genetics. Part A
Issue number12
Publication statusPublished - Dec 2021


  • FLNA
  • cardiomyopathy
  • filaminopathies
  • phenotype–genotype correlation
  • terminal osseous dysplasia with pigmentary defects


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