Unique prenatal manifestations of biallelic NDUFAF5 variants: expansion of phenotype

ABSTRACT 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 previousl...

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Published in:	Ultrasound in obstetrics & gynecology Vol. 63; no. 3; pp. 392 - 398
Main Authors:	Brabbing‐Goldstein, D., Kozlova, D., Bazak, L., Basel‐Salmon, L., Gilboa, Y., Marciano‐Levi, I., Zahra, J., Kanengisser‐Pines, B., Botvinik, A., Kurolap, A., Birnbaum, R., Yaron, Y.
Format:	Journal Article
Language:	English
Published:	Chichester, UK John Wiley & Sons, Ltd 01-03-2024 Wiley Subscription Services, Inc
Subjects:	Abnormalities Agenesis of Corpus Callosum Brain brain cysts Chromosome aberrations complex‐I deficiency Congenital defects corpus callosum Cysts Differential diagnosis Disorders Electron microscopy Electron Transport Complex I - deficiency exome sequencing Female Fetuses FGR Gynecology Hereditary diseases Humans Hydrops Fetalis Methyltransferases Microscopy Mitochondria Mitochondrial Diseases Mitochondrial Proteins - genetics NDUFAF5 Obstetrics Phenotype Phenotypes Pregnancy Proximal tubules Retrospective Studies Sequences Skeletal muscle Ultrasonic imaging FGR exome sequencing complex-I deficiency NDUFAF5 hydrops fetalis corpus callosum brain cysts
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Summary:	ABSTRACT 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. Linked article: There is a comment on this article by Finsterer. Click here to view the Correspondence.
Bibliography:	D.B.‐G., D.K., R.B. and Y.Y. contributed equally to the study. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0960-7692 1469-0705
DOI:	10.1002/uog.27482