Mitochondrial cardiomyopathy and ventricular arrhythmias associated with biallelic variants in C1QBP

Abstract

Patients with biallelic mutations in the nuclear-encoded mitochondrial gene C1QBP/ p32 have been described with syndromic features and autosomal recessive cardiomyopathy. We describe the clinical course in two siblings who developed cardiomyopathy and ventricular fibrillation in infancy. We provide genomic analysis and clinicalpathologic correlation. Both siblings had profound cardiac failure with ventricular arrhythmia. One child died suddenly. The second sibling survived resuscitation but required extracorporeal cardiopulmonary support and died shortly afterward. On cardiac autopsy, the left ventricle was hypertrophied in both children. Histological examination revealed prominent cardiomyocyte cytoplasmic clearing, and electron microscopy confirmed abnormal mitochondrial structure within cardiomyocytes. DNA sequencing revealed compound heterozygous variants in C1QBP (p.Thr40Asnfs*45 and p.Phe204Leu) in both children. Family segregation analysis demonstrated each variant was inherited from an unaffected, heterozygous parent. Inherited loss of C1QBP/p32 is associated with recessive cardiomyopathy, ventricular fibrillation, and sudden death in early life. Ultrastructural mitochondrial evaluation in the second child was similar to findings in engineered C1qbp-deficient mice. Rapid trio analysis can define rare biallelic variants in genes that may be implicated in sudden death and facilitate medical management and family planning. (184/200).

Complement C1q Binding Protein (C1QBP): Physiological Functions, Mutation-Associated Mitochondrial Cardiomyopathy and Current Disease Models

“…Table 2 summarizes the relative frequency of symptoms associated with biallelic variants in C1QBP and the relates the Human Phenotype Ontology (HPO) terms in which C1QBP mutatins should be suspected when a patient presents with cardiomyopathy, especially left ventricular hypertrophy, cardiomegaly, exercise tolerance, ptosis and PEO. The p.Phe204Leu mutation of the C1QBP protein was identified in four patients either in homozygosity (case 5) (21) or in compound heterozygosity (case 1, 11, 12) (20,24). The homozygous p.Phe204Leu mutation described in case 5 showed an adult onset mild phenotype, with PEO and mitochondrial myopathy.…”

“…Biallelic C1QBP mutation caused a COXPD 33 (OMIM:617713). In the reported 12 cases with C1QBP mutations, phenotypes were typically severe, even fatal (20)(21)(22)(23)(24). They present at any age and cover a wide spectrum of clinical manifestations including intrauterine growth restriction, cardiorespiratory arrest, cardiac hypertrophy, cardiac failure, ventricular arrhythmias, hepatomegaly, exercise intolerance, progressive external ophthalmoplegia (PEO), cerebral hemorrhages/edema and nervous system dysfunction.…”

“…The p.Phe204Leu mutation of the C1QBP protein was identified in four patients either in homozygosity (case 5) ( 21 ) or in compound heterozygosity (case 1, 11, 12) ( 20 , 24 ). The homozygous p.Phe204Leu mutation described in case 5 showed an adult onset mild phenotype, with PEO and mitochondrial myopathy.…”

“…Biallelic C1QBP mutations were recently identified manifesting as combined oxidative phosphorylation deficiency (COXPD) in an autosomal recessive inherited pattern. This involved multiple systems including heart, liver, skeletal muscle, eye and nervous system (20)(21)(22)(23)(24). However, cardiomyopathy, whose exact underlying mechanisms remain elusive, is the major phenotype.…”

End Stage Mitochondrial Cardiomyopathy and Heart Transplantation Due to Biallelic Pathogenic C1QBP Variants

“…Only 12 patients exhibiting biallelic C1QBP variants, manifesting with a broad spectrum of disease, have been reported. [1][2][3][4][5] Of these, several had skeletal and cardiac myopathies in addition to chronic progressive external ophthalmoplegia and lactic acidosis. Four patients were stillborn or died soon after birth due to fetal hydrops or heart failure.…”