oa Profile of rare developmental disabilities in a highly consanguineous Community: Research-based studies in Qatar

Developmental disabilities (DDs) are a diverse group of physical and mental impairments. Subjects with DDs almost suffer long lasting deficiencies in normal developmental milestones. Etiologies of DDs might look different in communities with high rate of consanguineous marriages, which increase the likelihood of hereditary monogenetic disorders, particularly the autosomal recessive (AR) ones. This study focuses on rare heritable disorders affecting either the normal movements or normal brain growth, in addition to other interesting monogenetic disorders. The study excludes common known causes of DDs as Down or fragile X syndromes or others. This study is aiming both to assess the contribution of rare AR heritable disorders to the burden of DDs in our population. And to better understanding of the clinical profile and molecular basis of DDs, particularly those evolved in consanguineous families. Early identification of the causative mechanism will not only delineate the management strategy and provide family recurrence risk but also it will help to outline primary preventive measures and introduce actions on how people with DDs can improve the quality of their lives. Patients and methods: A total of 62 families [308 individuals] were enrolled in three approved research grants, two NPRPs and a WCMCQ-Research BMRP, addressing: Hereditary Spastic Paraplegias (HSPs) as a group of movement disorders (ascertained in the period between 10/2012-July/2013], Teebi' monogenetic diseases in Qatari [2012-2013], and congenital brain malformation (CBM) [2011-2013] disorders. Patients were referred mostly from Pediatric Neurology, and also from genetic, physiotherapy, and adult Neurology departments of HMC, the largest referral hospital in Qatar. Genomics, bioinformatics and molecular biology studies were carried out at WCMCQ labs. Results: We identified 26 HSPs families [111 individuals], 14 families [75 individuals] with Teebi-monogenetic disorders, and 22 families [122 individuals] with congenital brain malformation. Demographic data: Patients' nationalities were: Qatari [~31%, 100%, &54% in HSP, Teebi' monogenetic, and CBM, respectively], Egyptian [~19% and 9% in HSP and CBM, respectively], Palestinian [~15% for HSPs], Omani [~ 11% &~ 5% in HSPs & CBM], and other nationalities [23% and ~32% in HSP & CBM, respectively]. Consanguineous marriages were in 20 HSP [77%], 14 Teebi' [100%], and 17 CBM [77%] families. Clinically: HSPs patients were subcategorize as AR-complex phenotype [~77% of HSP families], in which presentations of seizures, mental involvements, ataxia, extrapyramidal manifestation, optic atrophy or others were invariably associated, Autosomal dominant [15%] and X-linked [~8%]. Teebi' families were subcategorized as nine families [~64%] with neurologic disorders {hereditary neuropathy "pain insensitivity", vanishing white matter, dystonia, and seizure syndromes} and five independent families, each presents [~7%] with a neuromuscular, an autoimmune, a rare muscle disease, developmental delay with behavioral abnormalities, and mitochondrial disorder. CBM families showed variable forms of cortical and central brain malformation, calcification and migration defects. Genomic data: ten HSPs, twelve Teebi', and nine CBM, families were subjected to Whole Genome Sequence (WGS). Data are currently under bioinformatics and molecular biology studies. Plans are in place to WGS other families. Conclusion: Presented research can be enriched and integrated into the national health management and patients care systems.