Homozygosity mapping and targeted genomic sequencing reveal the gene responsible for cerebellar hypoplasia and quadrupedal locomotion in a consanguineous kindred

• DOI: 10.1101/gr.126110.111
• Publication Date: 2011-09-02T00:58:45Z
• Authors: Suleyman Gulsuner; Ayse Begum Tekinay; Katja Doerschner; Huseyin Boyaci; Kaya Bilguvar; Hilal Unal; Aslihan Ors; O. Emre Onat; Ergin Atalar; A. Nazli Basak; Haluk Topaloglu; Tulay Kansu; Meliha Tan; Uner Tan; Murat Gunel; Tayfun Ozcelik
• Keywords: Disease gene identification; Cerebellar hypoplasia (non-human)

The biological basis for the development of cerebro-cerebellar structures required posture and gait in humans is poorly understood. We investigated a large consanguineous family from Turkey exhibiting an extremely rare phenotype associated with quadrupedal locomotion, mental retardation, hypoplasia, linked to 7.1-Mb region homozygosity on chromosome 17p13.1–13.3. Diffusion weighted imaging fiber tractography patients' brains revealed morphological abnormalities cerebellum corpus callosum, particular atrophy superior, middle, inferior peduncles cerebellum. Structural magnetic resonance showed additional morphometric several cortical areas, including precentral gyrus, Brodmann areas BA6, BA44, BA45. Targeted sequencing entire homozygous three affected individuals two obligate carriers uncovered private missense mutation, WDR81 p.P856L, which cosegregated condition extended family. mutation lies highly conserved WDR81, flanked by N-terminal BEACH domain C-terminal WD40 beta-propeller domains. predicted be transmembrane protein. It expressed Purkinje cell layer represents third gene, after VLDLR CA8 , implicated locomotion humans.