Exome sequencing of patients with histiocytoid cardiomyopathy reveals a de novo NDUFB11 mutation that plays a role in the pathogenesis of histiocytoid cardiomyopathy.
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.
School of Medicine, Emory University, Atlanta, Georgia.
Bahig M
BM
Shehata
School of Medicine, Emory University, Atlanta, Georgia.|School of Biology, CSIR Georgia Institute of Technology, Atlanta, Georgia.
Caitlin A
CA
Cundiff
School of Biology, CSIR Georgia Institute of Technology, Atlanta, Georgia.
Kevin
K
Lee
Genomics and Molecular Medicine, Institute of Genomics and Integrative Biology, Delhi, India.|Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhavan, New Delhi, India.
Ankit
A
Sabharwal
Genomics and Molecular Medicine, Institute of Genomics and Integrative Biology, Delhi, India.
Mukesh Kumar
MK
Lalwani
School of Medicine, Emory University, Atlanta, Georgia.
Angela K
AK
Davis
School of Biology, CSIR Georgia Institute of Technology, Atlanta, Georgia.
Vartika
V
Agrawal
Genomics and Molecular Medicine, Institute of Genomics and Integrative Biology, Delhi, India.|Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhavan, New Delhi, India.
Sridhar
S
Sivasubbu
School of Medicine, Emory University, Atlanta, Georgia.
Glen J
GJ
Iannucci
School of Medicine, Emory University, Atlanta, Georgia.|School of Biology, CSIR Georgia Institute of Technology, Atlanta, Georgia.
Greg
G
Gibson
D000483:Alleles; D000818:Animals; D009202:Cardiomyopathies / Q000151:congenital* / Q000235:genetics; D018389:Codon, Nonsense / Q000235:genetics*; D004272:DNA, Mitochondrial / Q000235:genetics; D042967:Electron Transport Complex I / Q000235:genetics*; D014450:Electron Transport Complex III / Q000172:deficiency* / Q000235:genetics; D059472:Exome / Q000235:genetics*; D005260:Female; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D008297:Male; D024101:Mitochondrial Proteins / Q000235:genetics; D018832:Molecular Chaperones / Q000235:genetics; D009245:NADH Dehydrogenase / Q000235:genetics; D010375:Pedigree; D017422:Sequence Analysis, DNA / Q000379:methods; D015027:Zebrafish / Q000235:genetics
D018389:Codon, Nonsense; D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; D018832:Molecular Chaperones; C501824:NDUFAF2 protein, human; C518653:NDUFB11 protein, human; D009245:NADH Dehydrogenase; D042967:Electron Transport Complex I; C118906:NDUFB9 protein, human; D014450:Electron Transport Complex III
NDUFB11; de novo mutation; histiocytoid cardiomyopathy; morpholinos; whole exome sequencing; zebrafish