Early prenatal ventriculomegaly due to an AIFM1 mutation identified by linkage analysis and whole exome sequencing
Highlights
► Linkage analysis and whole exome sequencing identified a mutation in the AIFM1 gene. ► The report of a mutation in the AIFM1 gene, extending the clinical spectrum. ► AIFM1 mutation with fetal ventriculomegaly underscores complex I assembly importance. ► Linkage analysis followed by exome sequencing is a cost-effective approach. ► Especially for identification of mutations in small non-consanguineous families.
Introduction
Prenatal ventriculomegaly is usually the result of an altered development of the intracranial architecture with variable fluid pressure [1]. Investigation into the underlying causes is mostly confined to the accompanying anatomical findings [2]. Here, we employed linkage analysis followed by whole exome sequencing to identify the cause of familial prenatal ventriculomegaly. This recent approach is required because genomic regions linked to the phenotype by linkage analysis of a single, small family are generally multiple megabases long and contain hundreds of genes. The search for a single disease-causing mutation in the coding sequence of a large number of candidate genes has heretofore been an expensive and time-consuming process. The recent advances in DNA enrichment and next-generation sequencing technology have made it possible to quickly and cost-effectively sequence all coding exons (Exome), with subsequent rapid identification of alleles responsible for Mendelian disorders [3].
Section snippets
Patients
Patients A and B were brothers, born to healthy unrelated parents of Palestinian origin. There were no reported illnesses in neonates in the extended families. During routine sonographic examination performed at 13–14 weeks of the pregnancies of patients A and B, bilateral septated choroid plexus cysts were seen and brain lateral ventricles and the cisterna magna measurements were noted to be enlarged (15 mm and 12 mm, respectively). Repeated examinations revealed persistence of the brain
Results
The pattern of enzymatic deficiencies in muscle mitochondria suggested a defect in the synthesis of the mtDNA-encoded proteins. Quantification of mtDNA content relative to nuclear DNA in muscle tissue of patient A revealed a normal ratio (128% of the age-matched control), ruling out a defect in mtDNA synthesis and maintenance. The abundance of the 12S and 16S rRNA transcripts and of the COX2 mRNA, which together represent the various steps in mtDNA transcription, was normal in fibroblasts. This
Discussion
Three patients with prenatal ventriculomegaly followed by infantile encephalomyopathy in two were investigated for their disease causing mutation. Prenatal ventriculomegaly is the most frequent fetal brain anomaly found in routine sonographic screening during gestation [7]. While fetal imaging may reveal accompanying brain anomalies, mild ventriculomegaly as in our patients generally carries a favorable prognosis with postnatal normal development in up to 85% of cases [7], [8].
The severe muscle
Acknowledgments
We are grateful to Chaim Jalas at Bonei Olam Center for Rare Jewish Genetic Disorders, Brooklyn, NY for bioinformatic analysis, and to Alan J. Fox and Dr. Jonathan Schug for exome sequencing. The excellent technical assistance of Lital Sheva is greatly appreciated. This work was funded in part by Association Myologie Francaise (AFM) and by the Israeli Ministry of Health grant #5914.
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