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We have performed whole exome sequencing on five parent\u2010proband trios and identified nuclear\u2010encoded 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\u2010sense mutations in the second exon of the X\u2010linked nuclear gene <jats:italic>NDUFB11<\/jats:italic>. A third proband was doubly heterozygous for inherited rare variants in additional components of complex I, <jats:italic>NDUFAF2<\/jats:italic> and <jats:italic>NDUFB9<\/jats:italic>, 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 <jats:italic>NDUFB11<\/jats:italic> has not been implicated before in cardiac pathology, morpholino\u2010mediated knockdown of ndufb11 in zebrafish embryos generated defective cardiac tissue with cardiomegaly, looping defects, and arrhythmia which suggests the role of <jats:italic>NDUFB11<\/jats:italic> 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 <jats:italic>NDUFB11<\/jats:italic> mutation may cause a complex 1 deficiency in synergy with additional unknown mtDNA variants. \u00a9 2015 Wiley Periodicals, Inc.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ajmg.a.37138","type":"journal-article","created":{"date-parts":[[2015,4,29]],"date-time":"2015-04-29T11:15:28Z","timestamp":1430306128000},"page":"2114-2121","source":"Crossref","is-referenced-by-count":44,"title":["Exome sequencing of patients with histiocytoid cardiomyopathy reveals a de novo <i>NDUFB11<\/i> mutation that plays a role in the pathogenesis of histiocytoid cardiomyopathy"],"prefix":"10.1002","volume":"167","author":[{"given":"Bahig M.","family":"Shehata","sequence":"first","affiliation":[{"name":"School of Medicine Emory University Atlanta Georgia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caitlin A.","family":"Cundiff","sequence":"additional","affiliation":[{"name":"School of Medicine Emory University Atlanta 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