Exome sequencing of patients with histiocytoid cardiomyopathy reveals a de novo NDUFB11 mutation that plays a role in the pathogenesis of histiocytoid cardiomyopathy

Bahig M. Shehata*, Caitlin A. Cundiff, Kevin Lee, Ankit Sabharwal, Mukesh Kumar Lalwani, Angela K. Davis, Sridhar Sivasubbu, Glen J. Iannucci, Greg Gibson

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.

Original languageEnglish
Pages (from-to)2114-2121
Number of pages8
JournalAmerican Journal of Medical Genetics, Part A
Volume167
Issue number9
Early online date29 Apr 2015
DOIs
Publication statusPublished - 1 Sept 2015

Keywords / Materials (for Non-textual outputs)

  • De novo mutation
  • Histiocytoid cardiomyopathy
  • Morpholinos
  • NDUFB11
  • Whole exome sequencing
  • Zebrafish

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