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Objective: Mitochondrial complex-I deficiency, nuclear type 16, is a rare autosomal recessive disorder caused by biallelic pathogenic variants in NDUFAF5 (C20orf7) (OMIM 618238). The aim of this study was to describe a severe early prenatal manifestation of this disorder, which was previously considered to occur only postnatally., Methods: This was a multicenter retrospective case series including five fetuses from three non-related families, which shared common sonographic abnormalities, including brain cysts, corpus callosal malformations, non-immune hydrops fetalis and growth restriction. Genetic evaluation included chromosomal microarray analysis and exome sequencing. Two fetuses from the same family were also available for pathology examination, including electron microscopy., Results: Chromosomal microarray analysis revealed no chromosomal abnormality in any of the tested cases. Trio exome sequencing demonstrated that three affected fetuses from three unrelated families were compound heterozygous or homozygous for likely pathogenic variants in NDUFAF5. No other causative variants were detected. The association between NDUFAF5 variants and fetal malformations was further confirmed by segregation analysis. Histological evaluation of fetal tissues and electron microscopy of the skeletal muscle, liver, proximal tubules and heart demonstrated changes that resembled postmortem findings in 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. Mitochondrial complex-I disorders should be considered in the differential diagnosis of corpus callosal malformations and brain cysts, especially when associated with extracranial abnormalities, such as fetal growth restriction and non-immune hydrops fetalis. © 2023 International Society of Ultrasound in Obstetrics and Gynecology., (© 2023 International Society of Ultrasound in Obstetrics and Gynecology.)

The authors of the article titled "Unique prenatal manifestations of biallelic NDUFAF5 variants: expansion of phenotype" respond to comments made by Dr. Finsterer. They clarify that their study did not report on cases of intrauterine fetal death, but rather on cases of termination due to fetal anomalies. They also explain that functional or biochemical testing is not mandatory for determining variant pathogenicity according to the American College of Medical Genetics and Genomics guidelines. The authors provide evidence supporting the pathogenicity of the NDUFAF5 variants they studied and acknowledge the need for further research on one of the variants. They assert that their study contributes to the understanding of prenatal presentations of NDUFAF5-associated disorders and emphasize the challenges of studying prenatal phenotypes. The authors address Dr. Finsterer's mention of other possible abnormalities associated with NDUFAF5 variants and state that the lack of demonstration does not negate their assumption that these variants are causative of the congenital anomalies described in their study. They also clarify that family history and parental carrier status were included in their original manuscript. [Extracted from the article]

This has been discussed in detail in a recent systematic review by Mellis I et al i .[2], demonstrating that the incremental diagnostic yield of ES over CMA/karyotyping was 15% for non-selected fetal anomalies, 42% for selected anomalies and 17% for CNS anomalies. While patients were offered concurrent chromosomal microarray analysis (CMA) and exome sequencing (ES), most opted for termination of pregnancy even before receiving a genetic test result due to the severity of anomalies and because ES in pregnancy is currently not covered by the Israeli healthcare system. Even if the fetal phenotype may not appear to be severe enough to warrant termination of pregnancy, a genetic test result may point to a severe neurodevelopmental issue that has only mild physical manifestations. [Extracted from the article]