A novel homozygous variant in C1QBP causes severe IUGR, edema, and cardiomyopathy in two fetuses

Abstract

The C1QBP protein (complement component 1 Q subcomponent‐binding protein), encoded by the C1QBP gene, is a multifunctional protein predominantly localized in the mitochondrial matrix. Biallelic variants have previously been shown to give rise to combined respiratory‐chain deficiencies with variable phenotypic presentation, severity, and age at onset, from intrauterine with a mostly lethal course, to a late‐onset mild myopathy. We present two fetuses, one male and one female, of first‐cousin parents, with severe intrauterine growth retardation, oligo/anhydramnios, edema, and cardiomyopathy as the most prominent prenatal symptoms. Both fetuses showed no copy number variants by chromosome microarray analysis. Analysis of a fibroblast culture from one of the fetuses showed deficiency of respiratory chain complex IV, and using exome sequencing, we identified homozygosity for a novel variant in C1QBP in both fetuses. To our knowledge, only six patients with pathogenic variants in C1QBP have been reported previously and with this report, we add a novel pathogenic variant in C1QBP found in two related fetuses.

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

“…These three patients are all alive and show clinical phenotypes of left ventricular hypertrophy, exercise intolerance and ptosis ( 20 , 22 ). The homozygous p.Val248Ala mutations were described in case 9 and case 10 ( 23 ). They are associated with severe intrauterine growth restriction, edema, and cardiomyopathy.…”

“…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 compound heterozygous p.Phe204Leu and p.Cys186Ser mutation occurred in case 1, a newborn baby with cardiorespiratory arrest, asymmetric left ventricular cardiomegaly, multiple cortical, ventricular, and subdural hemorrhages, cerebral edema and burst suppression-like electrical discharges with subclinical seizures ( 20 ). The heterozygous frameshift c.118dupA insertion can result in a truncation mutation, p.Thr40Asnfs * 45, in the protein ( 23 ). The compound heterozygous p.Thr40Asnfs * 45 and p.Phe204Leu mutations were noted in two siblings (case 11 and 12) with ventricular arrhythmias, cardiac hypertrophy and cardiac arrest.…”

“…Spectrophotometric analysis of the mitochondrial respiratory chain complexes in muscle homogenates showed partially reduced complex I, III, and IV activities in case 5, whereas values were in the control range for case 6 ( 21 ). Alstrupet et al reported that the analysis of a fibroblast culture from one of the fetuses showed a deficiency of respiratory chain complex IV ( 23 ). The muscle biopsy analysis indicates that the degree of respiratory chain complex deficiency may correlate with phenotype and genotype.…”

“…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.…”