Publications

Published in “The Journal of Molecular Diagnostics” Volume 15, No. 6, p851 (Abstract number G32) Sandhoff disease is a rare, clinically heterogeneous, autosomal recessive lysosomal storage disease caused by mutations in the HEXB (hexosaminidase B) gene. Deficiency of beta-hexosaminidase A and B leads to excessive accumulation of GM2 ganglioside resulting in progressive neurodegeneration. The disease classically presents in infants who usually die by age 3 but rarely occurs in juveniles and adults. Juvenile Sandhoff disease typically presents between ages 2 and 10, and variable clinical manifestations include muscle weakness, ataxia and other movement disorders, progressive speech problems, seizures, visual problems, and intellectual impairment. In our study, we enrolled a large consanguineous Arab family with three siblings (two girls and one boy) affected by slowly progressive gait disturbance, action tremor, dysarthria, and mild intellectual disability. Chromosome analysis and Fragile X studies were normal in the male sibling. Autozygosity mapping using Affymetrix SNP Array 6.0 in the family members (3 affected and 2 unaffected siblings and unaffected parents) revealed two candidate loci: 5q13.2-q13.3 and 6p12.3-p21.2. Exome sequencing of three family members (mother, one affected boy, and one affected girl) to 50X average depth of coverage with 2x100 paired-end reads on Illumina HiSeq 2000 generated an average of 7.5 Gb of sequence for each sample. About 1,100 novel variants were annotated using the GenomeQuest whole genome analysis software. A homozygous c.1615C>T (p.Arg539Cys) mutation was identified in the HEXB gene located on the 5q13.3 homozygous region shared by all affected siblings, while mother was a heterozygous carrier. This novel variant is predicted to be deleterious by PolyPhen, SIFT, and Condel bioinformatics tools. Here, we report a novel homozygous missense HEXB gene mutation in three affected siblings from a consanguineous family with a late-onset form of Sandhoff disease. Missense mutations are the most common type of mutations in this gene. To date, about 84 mutations have been reported in HEXB and most of them cause the severe infant form of the disease. In light of the data obtained through exome sequencing, clinical re-evaluation of the affected siblings for a late-onset form of Sandhoff disease is in process. Our study highlights the importance of exome sequencing in the underlying molecular mechanisms of clinically heterogeneous known single-gene disorders.