Exome Sequencing of Patients with Histiocytoid Cardiomyopathy Reveals a de novo NDUFB11 Mutation That Plays a Role in the Pathogenesis of Histiocytoid Cardiomyopathy

• Type of Material: Article
• Authors: Bahig Shehata, Emory University; Kevin Lee, Georgia Institute of Technology; Ankit Sabharwal, Institute of Genomics and Integrative Biology; Mukesh Kumar Lalwani, Institute of Genomics and Integrative Biology; Caitlin A. Cundiff, Emory University; Angela K. Davis, Emory University; Vartika Agrawal, Georgia Institute of Technology; Sridhar Sivasubbu, Institute of Genomics and Integrative Biology; Greg Gibson, Emory University
• Language: English
• Date: 2015-09-01
• Publisher: WILEY
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2015 Wiley Periodicals, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1002/ajmg.a.37138
• Title of Journal or Parent Work: AMERICAN JOURNAL OF MEDICAL GENETICS PART A
• Volume: 167
• Issue: 9
• Start Page: 2114
• End Page: 2121
• Grant/Funding Information: KL was the recipient of a Presidential Fellowship from the Regents of the Georgia Institute of Technology.; AS acknowledges a junior research fellowship (JRF) from CSIR.; MKL acknowledges fellowship funding from BSC0123 grant of CSIR-IGIB.; GG is partially supported by Project 3 of NIGMS P01 GM099568 (B. Weir, U. Washington, PI).; The authors acknowledge funding from the Council of Scientific and Industrial Research (CSIR), India through the BSC0122 Grant.; Exome sequencing was supported by a private donor to BS.
• Keywords: Life Sciences & Biomedicine; INFANT; NDUFB11; DATABASE; DISEASE; de novo mutation; CANDIDATE GENES; zebrafish; Genetics & Heredity; whole exome sequencing; histiocytoid cardiomyopathy; morpholinos; Science & Technology; DEATH
• Research Categories: Biology, Genetics; Health Sciences, Medicine and Surgery

Abstract

Histiocytoid cardiomyopathy (Histiocytoid CM) is a rare form of cardiomyopathy observed predominantly in newborn females that is fatal unless treated early in life. We have performed whole exome sequencing on five parent-proband trios and identified nuclear-encoded mitochondrial protein mutations in three cases. The molecular genetic basis of Histiocytoid CM remains unknown despite several hypotheses in medical literature. The findings presented in this manuscript may represent components of genetic etiologies for this heterogeneous disease. Two probands had de novo non-sense mutations in the second exon of the X-linked nuclear gene NDUFB11. A third proband was doubly heterozygous for inherited rare variants in additional components of complex I, NDUFAF2 and NDUFB9, confirming that Histiocytoid CM is genetically heterogeneous. In a fourth case, the proband with Histiocytoid CM inherited a mitochondrial mutation from her heteroplasmic mother, as did her brother who presented with cardiac arrhythmia. Strong candidate recessive or compound heterozygous variants were not found for this individual or for the fifth case. Although NDUFB11 has not been implicated before in cardiac pathology, morpholino-mediated knockdown of ndufb11 in zebrafish embryos generated defective cardiac tissue with cardiomegaly, looping defects, and arrhythmia which suggests the role of NDUFB11 in the pathogenesis of this abnormal cardiac pathology. Taken together, the unbiased whole exome sequencing approach confirms the suspected genetic heterogeneity of Histiocytoid CM. Therefore, the novel NDUFB11 mutation may cause a complex 1 deficiency in synergy with additional unknown mtDNA variants.