Unique prenatal manifestations of biallelic NDUFAF5 variants: expansion of the phenotype

ABSTRACT Objectives Mitochondrial complex I deficiency, nuclear type 16 is a rare autosomal recessive disorder caused by biallelic pathogenic variants in NDUFAF5 ( C20orf7 ) [OMIM 618238]. This entity belongs to a genetically and clinically heterogenic group of complex I deficiency which accounts for up to 30% of childhood mitochondrial disorders presenting as Leigh syndrome, leukoencephalopathy, fatal infantile lactic acidosis, and other early‐onset neurodegenerative disorders. We present very early, unique, and severe prenatal manifestation of this disorder, previously considered to manifest post‐natally. Methods We describe five fetuses from three non‐related families sharing common sonographic abnormalities including brain cysts, callosal malformations, hydrops fetalis, and growth restriction. Genetic evaluation included chromosomal microarray analysis and exome sequencing. Two fetuses from one family were also available for pathology examination, including electronic microscopy. Results Chromosomal microarray revealed no chromosomal abnormalities. Trio exome sequencing demonstrated that three affected fetuses from three unrelated families were compound heterozygotes or homozygotes for likely pathogenic variants in NDUFAF5 . No other causative variants were detected. NDUFAF5 variants association with fetal malformations was further confirmed by segregation studies. Histologic evaluation of fetal tissues and electronic microscopy of muscle, liver, proximal tubules of kidney and heart, demonstrated changes resembling those described in postmortem autopsies of patients with mitochondrial depletion disorders as well as previously undescribed findings. Conclusions Mitochondrial complex I deficiency and specifically biallelic mutations in NDUFAF5 have a role in abnormal fetal development presenting with severe congenital malformations. Complex I mitochondrial disorders should be considered in the differential diagnosis of callosal malformations and brain cysts, especially when associated with extra central nervous system (CNS) abnormalities such as fetal growth restriction or nonimmune hydrops fetalis. This article is protected by copyright. All rights reserved.