2014 May 15;340(1-2):86-90. doi: 10.1016/j.jns.2014.02.033. Epub 2014 Mar 4.

Author information

1
Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan.
2
Cancer Genomics Project, Graduate School of Medicine, University of Tokyo, Tokyo, Japan; Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
3
Cancer Genomics Project, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
4
Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
5
Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
6
Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
7
Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan. Electronic address: m.takagi.ped@tmd.ac.jp.

Abstract

A number of diseases exhibit neurodegeneration with/without additional symptoms such as immunodeficiency, increased cancer risk, and microcephalus. Ataxia telangiectasia and Nijmegen breakage syndrome, for example, develop as a result of mutations in genes involved in the DNA damage response. However, such diseases can be difficult to diagnose as they are only rarely encountered by physicians. To overcome this challenge, nine patients with symptoms that resemble those of ataxia telangiectasia, including neurodegeneration, hypogammaglobulinemia, telangiectasia, and/or elevated serum α-fetoprotein, were subjected to whole-exome sequencing (WES) to identify the causative mutations. Molecular diagnosis was achieved in two patients: one displayed CD40 ligand (CD40LG) deficiency, while a second showed a homozygous SIL1 mutation, which has been linked to Marinesco-Sjögren syndrome (MSS). Typical features of CD40LG deficiency and MSS are distinct from the symptoms usually seen in ataxia telangiectasia. These dissociations between phenotype and genotype make it difficult to achieve molecular diagnosis of orphan diseases. Whole-exome sequencing analyses will assist in the molecular diagnosis of such cases and allow the identification of genotypes that would not be expected from the phenotype.

KEYWORDS:

CD40 ligand; DNA damage; Immunodeficiency; Neurodegeneration; SIL1; Whole-exome sequencing

PMID:
 
24631270
 
DOI:
 
10.1016/j.jns.2014.02.033
[Indexed for MEDLINE]