טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentKurolap Alina
SubjectPeripheral Neuropathy Associated with Mental Deficiency -
Homozygosity Mapping and Gene Identification
DepartmentDepartment of Medicine
Supervisors Clinical Professor Ruth Gershoni-Baruch
Dr. Efrat Dagan
Full Thesis textFull thesis text - English Version


Abstract

Background: This study sought to identify the causative mutation of a recessively inherited syndrome characterized by peripheral neuropathy and mental retardation, in an extended consanguineous Muslim Israeli-Arab family. Peripheral neuropathy results from axonal or demyelinative nerve damage, and manifests as a motor, sensory or autonomic disorder. The most common hereditary sensory-motor peripheral neuropathy is Charcot-Marie-Tooth (CMT). Diseases other than CMT, such as hereditary spastic paraplegia (HSP), may occasionally manifest peripheral sensory-motor damage. Peripheral neuropathy is genetically and phenotypically heterogeneous, with over 50 causative loci and genes identified. The clinical presentation varies even within the same family, thus, making clinical and molecular diagnosis challenging.

Methods: Molecular genetic diagnosis by whole-genome homozygosity mapping and linkage analysis using Illumina’s HumanLinkage-12 BeadChip (6K SNP) and HumanCytoSNP-12 BeadChip (300K SNP) arrays was attempted. Additionally, we performed whole-exome sequencing in one patient.

Results: A 6K SNP array analysis in four affected individuals and eight healthy family members yielded over 300 candidate areas of homozygosity, with a highest LOD score of 2.4. Regions with highest LOD scores or containing candidate genes were excluded using microsatellite markers. A 300K SNP array analysis in two affected individuals and their mother narrowed the candidate areas to 11 essentials. Whole-exome analysis of an affected individual was undertaken. A missense mutation in the SPG7 gene (implicated in autosomal recessive HSP associated with peripheral neuropathy) was identified, but it did not segregate appropriately within the family. We subsequently evaluated other non-synonymous and non-coding variants, as well as Sanger sequenced poorly covered exons, in parallel to the linkage analysis described above. Nevertheless, the culprit remains unknown and further research is required.