Early prenatal ventriculomegaly due to an AIFM1 mutation identified by linkage analysis and whole exome sequencing

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Abstract

The identification of disease causing mutation in patients with neurodegenerative disorders originating from small, non-consanguineous families is challenging. Three siblings were found to have ventriculomegaly at early gestation; postnatally, there was no acquisition of developmental milestones, and the muscles of the children were dystrophic. Plasma and CSF lactate levels were normal, but the activities of mitochondrial complex I and IV were markedly decreased. Using linkage analysis in the family, followed by whole exome sequencing of a single patient, we identified a pathogenic mutation in the AIFM1 gene which segregated with the disease state and was absent in 86 anonymous controls. This is the second report of a mutation in the AIFM1 gene, extending the clinical spectrum to include prenatal ventriculomegaly and underscores the importance of AIF for complex I assembly. In summary, linkage analysis followed by exome sequencing of a single patient is a cost-effective approach for the identification of disease causing mutations in small non-consanguineous families.

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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