Exome sequencing of two patients in a family with atypical X‐linked leukodystrophy

Abstract

We encountered a family with two boys similarly showing brain atrophy with reduced white matter, hypoplasia of the brain stem and corpus callosum, spastic paralysis, and severe growth and mental retardation without speaking a word. The phenotype of these patients was not compatible with any known type of syndromic leukodystrophy. Presuming an X-linked disorder, we performed next-generation sequencing (NGS) of the transcripts of the entire X chromosome. A single lane of exome NGS in each patient was sufficient. Six potential mutations were found in both affected boys. Two missense mutations, including c.92T>C (p.V31A) in L1CAM, were potentially pathogenic, but this remained inconclusive. The other four could be excluded. Because the patients did not show adducted thumbs or hydrocephalus, the L1CAM change in this family can be interpreted as different scenarios. Personal genome analysis using NGS is certainly powerful, but interpretation of the data can be a substantial challenge requiring a lot of tasks.

Exome sequencing in a family with an X‐linked lethal malformation syndrome: clinical consequences of hemizygous truncating OFD1 mutations in male patients

“…Heterozygous truncating OFD1 mutations preserving normal exons 1-16 have been reported in only two families with typical female OFD1 patients: a single-base deletion (c.2349delC in exon 17, p.Ileu784Serfs*85) (20) and a deletion of complete exon 17 (21). We have also identified two possible but inconclusive missense variants (L1CAM and TMEM187 ) in a family with an atypical X-linked leukodystrophy from only two affected male samples (25). High-throughput, next-generation sequencing (NGS) has had a tremendous impact on human genetic research (22).…”

“…We recently identified a nonsense mutation in MCT8 causing X‐linked leukoencephalopathy in a family from only two affected male samples (24). We have also identified two possible but inconclusive missense variants ( L1CAM and TMEM187 ) in a family with an atypical X‐linked leukodystrophy from only two affected male samples (25). In this study, exome sequencing accompanied by appropriate bioinformatics techniques and a co‐segregation evaluation successfully revealed a disease‐causing mutation in OFD1 , which could not have been assumed to be a candidate based on the clinical manifestations of the affected male patients.…”

The Use of Next-Generation Sequencing in Movement Disorders

“…Likewise, SLC16A2 genetic variability, which was already implicated in X-linked mental retardation, Allan–Herndon–Dudley syndrome, and Pelizaeus–Merzbacher-like disease (Friesema et al, 2004; Dumitrescu et al, 2006; Frints et al, 2008; Vaurs-Barriere et al, 2009), has recently been associated with a X-linked form of leukoencephalopathy, clinically diagnosed as PMD (Tsurusaki et al, 2011). Although SLC16A2 encodes a thyroid hormone transporter known as monocarboxylate transporter 8, MCT8, none of PMD patients carrying SLC16A2 mutations reported thyroid dysfunction.…”

Neurological disorders, genetic correlations, and the role of exome sequencing

“…Unable to identify a contributory mutation by using traditional polymerase chain reaction (PCR)-sequencing in their study of the brain demyelinating disorder called X-linked leucoencephalopathy, a group of researchers subsequently applied exome sequencing to only one lane of material and obtained enlightening results [10]. The disorder affects myelin-the material responsible for brain matter being designated as white matter instead of grey.…”

“…Whether examining the mitochondrial defect implicated in prenatal ventriculomegaly [7], the often early-stage atypical presentation of neurocanthocytosis [8], or the fatal amyotrophic lateral sclerosis [9], scientists recognize that exome sequencing "potentially widens the clinical spectrum associated with Amyotrophic Lateral Sclerosis (ALS) to include bone dysfunction and myopathy, and provides further insight into the importance of cellular protein degradation pathways…." [9].Unable to identify a contributory mutation by using traditional polymerase chain reaction (PCR)-sequencing in their study of the brain demyelinating disorder called X-linked leucoencephalopathy, a group of researchers subsequently applied exome sequencing to only one lane of material and obtained enlightening results [10]. The disorder affects myelin-the material responsible for brain matter being designated as white matter instead of grey.…”