Heart‐hand syndrome IV: a second family with LMNA‐related cardiomyopathy and brachydactyly

Abstract

Clin Genet 2017: 91: 499–500 Printed in Singapore. All rights reserved CLINICAL GENETICS doi: 10.1111/cge.12870 Letter to the Editor Heart-hand syndrome IV: a second family with LMNA-related cardiomyopathy and brachydactyly To the Editor: Heart-hand syndromes (HHS) include the most com- mon type – HHS I: Holt–Oram syndrome (congenital heart disease and radial ray anomalies) and several rare types – HHS II: Tabatznik syndrome (arrhythmias and brachytelephalangy), HHS III: Spanish type (arrhyth- mia and brachydactyly type C), and a potential HHS IV: Slovenian type [arrhythmia, dilated cardiomyopa- thy (DCM), and brachydactyly] (1, 2). TBX5 for HHS I: Holt–Oram syndrome and LMNA for HHS-Slovenian type (due to a cryptic splice-site mutation) are the only two genes found to contribute to HHS (1–3). We report a second HHS IV family due to a previ- ously reported LMNA mutation (p.Arg335Trp). All pro- cedures were approved by the UCI institutional review board. Written informed consent was obtained for all participants. The proband, who recently died at age 57, had DCM and ‘small hands.’ His family had Ger- man and Irish ancestry and multiple individuals born with ‘small hands’ and later developed heart disease. Eleven individuals were classified as affected or unaf- fected for heart disease (4) and hand anomalies (Fig. S1 and Table S1, Supporting Information). Characteriza- tion of the hands and feet for the proband (III-6) and his affected first-cousin (III-11) revealed small hands with short digital rays (Fig. 1a). Hand radiographs showed shortened digital rays with no carpal anomalies (Fig. 1b), and metacarpophalangeal pattern (MCPP) profile analy- sis (5) revealed a consistent wavy pattern with brachy- dactyly of all tubular bones with marked shortening of the first and third distal phalanges, second middle phalanx and first proximal phalanx (Fig. 1c). For both patients, the feet were normal in appearance with normal radiographs (not shown). In addition, there were no signs of myopathy or lipodystrophy. To identify the causative variant(s) for the cardiac and/or limb phenotypes, exome sequencing for the proband was conducted (4). The results included 14 giga- bases of data from 164 million reads, 91% of mapped reads to hg19, and 134X average read coverage of each exon. To identify high-priority candidate variants from 10,395 variants predicted to impact the protein, we focused on variants located in candidate genes associated with cardiomyopathy, arrhythmia, ion channels, or limb anomalies (Table S2). Ten candidates were identified (Table S3) and validated by Sanger sequencing. Fam- ily studies to determine co-segregation identified LMNA c.1003C>T, p.Arg335Trp [RefSeq NM_170707.3], a heterozygous C>T missense variant in exon 6 as the pri- mary mutation for both the cardiac and limb phenotypes (Figs S2 and S3). With similar cardiac and skeletal features as the HHS-Slovenian family (2), we provide further evidence for a fourth type of HHS due to a LMNA mutation. In both families, the cardiac features are typical for LMNA-related cardiac disease (2), and the skeletal fea- tures evaluated by MCPP profile analysis displayed a similar wavy pattern with brachydactyly affecting all the tubular bones of the hands with more severely affected first and third distal phalanges and first proximal pha- lanx (2). Differences between the families were noted. Patients in the Slovenian family presented in the fourth to fifth decades with cardiac disease (2) while patients in our family often presented younger: daughter (IV-13) with syncope at age 12, nephew (IV-16) with cardio- genic shock at age 27, and sister with sudden death at age 23. Differences in skeletal features included severe foot involvement as short or absent phalanges, short metatarsal bones, and IV–V syndactyly in the Slovenian family (2) while our family showed no significant foot abnormalities. Patients with LMNA c.1003C>T (p.Arg335Trp) and cardiac disease have been published; however, limb anomalies were not reported (ClinVar: Variation ID:36473 and Leiden Open Variation Database DB-ID LMNA_00127). This includes a heterozygous patient with atrial fibrillation, hypertriglyceridemia, mus- cle weakness, and acro-osteolysis. LMNA-associated acro-osteoylsis has been seen in autosomal recessive mandibuloacral dysplasia (OMIM 248370). The more severe involvement of the distal phalanges seen in both families and acro-osteolysis seen in other LMNA patients suggests an increased susceptibility of the distal limb elements to disturbances in LMNA dosage. The reasons for the clinical variability are not known. In the Slovenian family, a heterozygous cryptic splice-site mutation LMNA c.1609-12T>G was found; expression studies showed abnormal mRNA splicing and a truncated Lamin A/C protein with 14 new amino acids at the C-terminus (p.E536fsX14) consistent with © 2016 The Authors. Clinical Genetics published by John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.