ESPE Abstracts

Background: Woodhouse-Sakati syndrome (WSS) is rare autosomal recessive condition characterized by progressive extrapyramidal signs, mental retardation, hypogonadism, alopecia, and diabetes mellitus. The age at disease onset, manifestation and severity of specific symptoms differs significantly among individuals with this syndrome and even among affected members of the same family. The gene C2orf37, which is responsible for WSS, located on chromosome 2q22.3-q35.

Objective(s): To describe the clinical and genetic characteristics of Woodhouse-Sakati Syndrome diagnosed in three siblings from the state of Qatar.

Clinical history/methods: The phenotype of the three siblings included hypogonadism, alopecia, diabetes mellitus, and different degrees of mental retardation ranging from mild to severe. Whole Exome Sequencing (WES) analysis was performed in the index patient and her parents. Using genomic DNA, the exonic region and flanking splice junctions of the genome were captured and sequenced by NetGen sequencing on an Illumina system. Sequence variants were analyzed using Xome Analyzer. Capillary sequencing was used to confirm all possibly pathogenic variants. Sequence and copy number alterations were reported according to the Human Genome Variation Society (HGVS) and International System for human Cytogenetic Nomenclature (ISCN) guideline, respectively.

Results: Homozygous mutation c.436delC in exon 4 in the DCAF17 gene was identified in all the three siblings. Both parents were heterozygous for the mutations. C2orf37 codes for DCAF17 (DDB1 and CUL4 associated factor 17) a transmembrane protein that localizes to the nuclear envelop of unknown function but that may be associated with the ubiquitin system. C2orf17 codes for a protein of 520 aa. The c.436DelC mutation causes a frame shift and a predicted truncated protein of 147 aa.

Conclusion: Mutations in DCAF17 account for the features of Woodhouse-Sakati syndrome, however, the exact mechanisms of the hormonal abnormalities and the other signs and symptoms remain unclear. Understanding the molecular basis of WSS will provide novel insights into the role of the C2orf37 gene in normal physiology. In relation to the endocrine manifestations, understanding the role of C2orf37 gene in diabetes mellitus, hypogonadism and hypothyroidism will provide insights into the function of the pancreas, gonads and the thyroid gland respectively. The translational implications of this are that we might be able to develop novel therapies for this disorder if we know how mutations in C2orf37 gene lead to the multiple endocrine manifestations.