TY - JOUR
T1 - Terminal osseous dysplasia with pigmentary defects and cardiomyopathy caused by a novel FLNA variant
AU - Rumping, Lynne
AU - Wessels, Marja W.
AU - Postma, Alex V.
AU - van Schuppen, Joost
AU - van Slegtenhorst, Marjon A.
AU - Saris, Jasper J.
AU - van Tintelen, J. Peter
AU - Robertson, Stephen P.
AU - Alders, Mariëlle
AU - Maas, Saskia M.
AU - Deprez, Ronald H. Lekanne
N1 - Funding Information: We are grateful for the contribution of the patient's family to this study. We would like to thank Marloes Willemsen, Maureen Rahanra and Naomi Donner (Academic Medical Centre Amsterdam) for their great technical assistance. We thank Emma Wade and Kaya Fukushima (University of Otago, New Zealand) for helpful discussions. This project has not been funded. The parents of the proband have given informed consent for publication of the medical data and pictures. Publisher Copyright: © 2021 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
KW - FLNA
KW - cardiomyopathy
KW - filaminopathies
KW - phenotype–genotype correlation
KW - terminal osseous dysplasia with pigmentary defects
UR - http://www.scopus.com/inward/record.url?scp=85109660926&partnerID=8YFLogxK
U2 - https://doi.org/10.1002/ajmg.a.62417
DO - https://doi.org/10.1002/ajmg.a.62417
M3 - Article
C2 - 34254723
SN - 1552-4825
VL - 185
SP - 3814
EP - 3820
JO - American journal of medical genetics. Part A
JF - American journal of medical genetics. Part A
IS - 12
ER -