Integrated Analysis of Whole Exome Sequencing and Copy Number Evaluation in Parkinson's Disease.

Genetic studies of the familial forms of Parkinson's disease (PD) have identified a number of causative genes with an established role in its pathogenesis. These genes only explain a fraction of the diagnosed cases. The emergence of Next Generation Sequencing (NGS) expanded the scope of rare variants identification in novel PD related genes. In this study we describe whole exome sequencing (WES) genetic findings of 60 PD patients with 125 variants validated in 51 of these cases. We used strict criteria for variant categorization that generated a list of variants in 20 genes. These variants included loss of function and missense changes in 18 genes that were never previously linked to PD (NOTCH4, BCOR, ITM2B, HRH4, CELSR1, SNAP91, FAM174A, BSN, SPG7, MAGI2, HEPHL1, EPRS, PUM1, CLSTN1, PLCB3, CLSTN3, DNAJB9 and NEFH) and 2 genes that were previously associated with PD (EIF4G1 and ATP13A2). These genes either play a critical role in neuronal function and/or have mouse models with disease related phenotypes. We highlight NOTCH4 as an interesting candidate in which we identified a deleterious truncating and a splice variant in 2 patients. Our combined molecular approach provides a comprehensive strategy applicable for complex genetic disorders.

Whole exome sequencing reveals inherited and de novo variants in autism spectrum disorder: a trio study from Saudi families.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with genetic and clinical heterogeneity. The interplay of de novo and inherited rare variants has been suspected in the development of ASD. Here, we applied whole exome sequencing (WES) on 19 trios from singleton Saudi families with ASD. We developed an analysis pipeline that allows capturing both de novo and inherited rare variants predicted to be deleterious. A total of 47 unique rare variants were detected in 17 trios including 38 which are newly discovered. The majority were either autosomal recessive or X-linked. Our pipeline uncovered variants in 15 ASD-candidate genes, including 5 (GLT8D1, HTATSF1, OR6C65, ITIH6 and DDX26B) that have not been reported in any human condition. The remaining variants occurred in genes formerly associated with ASD or other neurological disorders. Examples include SUMF1, KDM5B and MXRA5 (Known-ASD genes), PRODH2 and KCTD21 (implicated in schizophrenia), as well as USP9X and SMS (implicated in intellectual disability). Consistent with expectation and previous studies, most of the genes implicated herein are enriched for biological processes pertaining to neuronal function. Our findings underscore the private and heterogeneous nature of the genetic architecture of ASD even in a population with high consanguinity rates.

The landscape of genetic diseases in Saudi Arabia based on the first 1000 diagnostic panels and exomes.

In this study, we report the experience of the only reference clinical next-generation sequencing lab in Saudi Arabia with the first 1000 families who span a wide-range of suspected Mendelian phenotypes. A total of 1019 tests were performed in the period of March 2016-December 2016 comprising 972 solo (index only), 14 duo (parents or affected siblings only), and 33 trio (index and parents). Multigene panels accounted for 672 tests, while whole exome sequencing (WES) represented the remaining 347 tests. Pathogenic or likely pathogenic variants that explain the clinical indications were identified in 34% (27% in panels and 43% in exomes), spanning 279 genes and including 165 novel variants. While recessive mutations dominated the landscape of solved cases (71% of mutations, and 97% of which are homozygous), a substantial minority (27%) were solved on the basis of dominant mutations. The highly consanguineous nature of the study population also facilitated homozygosity for many private mutations (only 32.5% of the recessive mutations are founder), as well as the first instances of recessive inheritance of previously assumed strictly dominant disorders (involving ITPR1, VAMP1, MCTP2, and TBP). Surprisingly, however, dual molecular diagnosis was only observed in 1.5% of cases. Finally, we have encountered candidate variants in 75 genes (ABHD6, ACY3, ADGRB2, ADGRG7, AGTPBP1, AHNAK2, AKAP6, ASB3, ATXN1L, C17orf62, CABP1, CCDC186, CCP110, CLSTN2, CNTN3, CNTN5, CTNNA2, CWC22, DMAP1, DMKN, DMXL1, DSCAM, DVL2, ECI1, EP400, EPB41L5, FBXL22, GAP43, GEMIN7, GIT1, GRIK4, GRSF1, GTRP1, HID1, IFNL1, KCNC4, LRRC52, MAP7D3, MCTP2, MED26, MPP7, MRPS35, MTDH, MTMR9, NECAP2, NPAT, NRAP, PAX7, PCNX, PLCH2, PLEKHF1, PTPN12, QKI, RILPL2, RIMKLA, RIMS2, RNF213, ROBO1, SEC16A, SIAH1, SIRT2, SLAIN2, SLC22A20, SMDT1, SRRT, SSTR1, ST20, SYT9, TSPAN6, UBR4, VAMP4, VPS36, WDR59, WDYHV1, and WHSC1) not previously linked to human phenotypes and these are presented to accelerate post-publication matchmaking. Two of these genes were independently mutated in more than one family with similar phenotypes, which substantiates their link to human disease (AKAP6 in intellectual disability and UBR4 in early dementia). If the novel candidate disease genes in this cohort are independently confirmed, the yield of WES will have increased to 83%, which suggests that most "negative" clinical exome tests are unsolved due to interpretation rather than technical limitations.