Catherine L Mercer1, Gaia Andreoletti1, Aisling Carroll2, Anthony P Salmon2, I Karen Temple2, Sarah Ennis2. 1. From the Wessex Clinical Genetics Service (C.L.M., I.K.T.) and Wessex Cardiac Unit (A.C., A.P.S.), University Hospital Southampton National Health Service Foundation Trust, United Kingdom; and Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, United Kingdom (G.A., I.K.T., S.E.). catherine.mercer@uhs.nhs.uk. 2. From the Wessex Clinical Genetics Service (C.L.M., I.K.T.) and Wessex Cardiac Unit (A.C., A.P.S.), University Hospital Southampton National Health Service Foundation Trust, United Kingdom; and Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, United Kingdom (G.A., I.K.T., S.E.).
Abstract
BACKGROUND: Familial Ebstein anomaly is a rare form of congenital heart disease. We report 7 individuals among 2 generations of 1 family with Ebstein anomaly. This family was first reported in 1991 by Balaji et al in which family members were also reported to have a mild skeletal phenotype. The most likely mechanism of inheritance was concluded to be autosomal dominant. We sought to identify the genetic pathogenesis in this family using a next generation sequencing approach. METHODS AND RESULTS: Whole exome sequencing was performed in 2 cousins in this family using the Agilent SureSelect Human all Exon 51 Mb version 5 capture kit. Data were processed through an analytic in-house pipeline. Whole exome sequencing identified a missense mutation in FLNA (Filamin A), an actin-binding protein located at Xq28, mutations in which are associated with the skeletal phenotypes Frontometaphyseal dysplasia, Otopalatodigital, and Melnick-Needles syndrome, with X-linked periventricular nodular heterotopia and FG syndrome (Omim, 305450). Review of the phenotypes of those with the mutation in this family shows increased severity of the cardiac phenotype and associated skeletal features in affected males, consistent with X-linked inheritance. CONCLUSIONS: Although congenital heart disease is reported in families with mutations in FLNA, this is the first report of individuals being affected by Ebstein anomaly because of a mutation in this gene and details the concurrent skeletal phenotype observed in this family.
BACKGROUND: Familial Ebstein anomaly is a rare form of congenital heart disease. We report 7 individuals among 2 generations of 1 family with Ebstein anomaly. This family was first reported in 1991 by Balaji et al in which family members were also reported to have a mild skeletal phenotype. The most likely mechanism of inheritance was concluded to be autosomal dominant. We sought to identify the genetic pathogenesis in this family using a next generation sequencing approach. METHODS AND RESULTS: Whole exome sequencing was performed in 2 cousins in this family using the Agilent SureSelect Human all Exon 51 Mb version 5 capture kit. Data were processed through an analytic in-house pipeline. Whole exome sequencing identified a missense mutation in FLNA (Filamin A), an actin-binding protein located at Xq28, mutations in which are associated with the skeletal phenotypes Frontometaphyseal dysplasia, Otopalatodigital, and Melnick-Needles syndrome, with X-linked periventricular nodular heterotopia and FG syndrome (Omim, 305450). Review of the phenotypes of those with the mutation in this family shows increased severity of the cardiac phenotype and associated skeletal features in affected males, consistent with X-linked inheritance. CONCLUSIONS: Although congenital heart disease is reported in families with mutations in FLNA, this is the first report of individuals being affected by Ebstein anomaly because of a mutation in this gene and details the concurrent skeletal phenotype observed in this family.
Authors: Sai Suma K Samudrala; Lauren M North; Karl D Stamm; Michael G Earing; Michele A Frommelt; Richard Willes; Swarnendu Tripathi; Nikita R Dsouza; Michael T Zimmermann; Donna K Mahnke; Huan Ling Liang; Michael Lund; Chien-Wei Lin; Gabrielle C Geddes; Michael E Mitchell; Aoy Tomita-Mitchell Journal: Mol Genet Genomic Med Date: 2020-01-27 Impact factor: 2.183
Authors: Suma K Thareja; Michele A Frommelt; Joy Lincoln; John W Lough; Michael E Mitchell; Aoy Tomita-Mitchell Journal: J Cardiovasc Dev Dis Date: 2022-04-13