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

Abstract

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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00439-017-1821-8) contains supplementary material, which is available to authorized users.

Warsaw breakage syndrome: Further clinical and genetic delineation

“…We conclude that the homozygous variant in MARS2 gene is the cause of the cerebellar abnormalities in patient 5. Thus, this likely represents a dual molecular diagnosis, which has been reported before especially in the setting of consanguinity [Monies et al, 2017; Yavarna et al, 2015]. …”

Next generation sequencing identifies double homozygous mutations in two distinct genes (EXPH5 and COL17A1 ) in a patient with concomitant simplex and junctional epidermolysis bullosa

“…Similarly, Monies et al. () reported that dual molecular diagnosis was rare and only accounted for 1.5% of cases subjected to WES. These relatively low numbers could be attributed to the methodology because dual diagnosis was considered only if both molecular lesions could be classified as at least likely pathogenic.…”

“…The diagnostic WES provides the opportunity to investigate the relationships between multi‐locus genomic variations and complex phenotypes, such as the presence of more than one Mendelian disease in one patient. Previous reports have shown the existence of multiple genetic diseases in up to 5% of the genetic patients referred to studies (Monies et al., ; Posey et al., ; Trujillano et al., ). In most cases, two diseases in a person have been recognized with distinct patterns of clinical manifestations, but in some occasions, concurrent diseases have overlapping phenotypic features.…”

Novel candidate genes and variants underlying autosomal recessive neurodevelopmental disorders with intellectual disability

“…In several published cohorts consisting of predominantly consanguineous ARID families from the Middle East and Pakistan (number of families ranging from 18 to 337), detection rates of putatively causal variants from NGS studies range from 37 to 90% and an aggregate of 327 novel or candidate ARID genes were identified (Najmabadi et al 2011; Yavarna et al 2015; Charng et al 2016; Megahed et al 2016; Riazuddin et al 2017; Anazi et al 2017; Reuter et al 2017; Harripaul et al 2017; Monies et al 2017; Hu et al 2018). …”