International Cooperation to Enable the Diagnosis of All Rare Genetic Diseases

Boycott, Kym M.; Rath, Ana; Chong, Jessica X.; Hartley, Taila; Alkuraya, Fowzan S.; Baynam, Gareth; Brookes, Anthony J.; Brudno, Michael; Carracedo, Ángel; Dunnen, Johan T. den; Dyke, Stephanie O.M.; Estivill, Xavier; Goldblatt, Jack; Gonthier, Catherine; Groft, Stephen C.; Gut, Marta; Hamosh, Ada; Hieter, Philip; Höhn, Sophie; Hurles, Matthew E.; Kaufmann, Petra; Knoppers, Bartha Maria; Krischer, Jeffrey P.; Maçek, Milan; Matthijs, Gert; Olry, Annie; Parker, Samantha; Paschall, Justin; Philippakis, Anthony; Rehm, Heidi L.; Robinson, Peter N.; Sham, Pak C.; Стефанов, Румен; Taruscio, Domenica; Unni, Divya; Vanstone, Megan R.; Zhang, Feng; Brunner, Han G.; Bamshad, Michael J.; Lochmüller, Hanns

doi:10.1016/j.ajhg.2017.04.003

Cited by 354 publications

(292 citation statements)

References 61 publications

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“…The final percentage of genes that are linked to Mendelian phenotypes remains a highly contested speculation (Boycott et al 2017). However, large iterative sequencing efforts from the same population can provide helpful clues in this regard.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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“…These advances will be optimised if there is international collaboration in the contribution to, and curation of, databases of variants 41. Beyond this, our knowledge of how the genome functions (in health and disease) will expand through the development of other ‘omics’ fields or so-called ‘multi-omics’ research initiatives 42…”

Section: Futurementioning

confidence: 99%

Genomics for paediatricians: promises and pitfalls

2018

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In recent years, there have been significant advances in genetic technologies, evolving the field of genomics from genetics. This has huge diagnostic potential, as genomic testing increasingly becomes part of mainstream medicine. However, there are numerous potential pitfalls in the interpretation of genomic data. It is therefore essential that we educate clinicians more widely about the appropriate interpretation and utilisation of genomic testing.

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“…. Whole-exome sequencing (WES) has become a frontline molecular detection technique for diagnosis of Mendelian disorders in neonatal and pediatric patients (Bamshad et al, 2012;Boycott et al, 2017;Choi et al, 2009;Stark et al, 2016). The success rate of using WES to identify causal mutations in patients referred by pediatricians and adult clinics is estimated to be approximately 25% (Yang et al, 2013(Yang et al, , 2014.…”

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confidence: 99%

Trio‐whole‐exome sequencing and preimplantation genetic diagnosis for unexplained recurrent fetal malformations

et al. 2019

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Whole-exome sequencing (WES) is widely used to detect genetic mutations that cause Mendelian diseases, and has been successfully applied in combination with preimplantation genetic diagnosis (PGD) to avoid the transmission of genetic defects.We investigated 40 nonconsanguineous families with unexplained, recurrent fetal malformations (two or more malformed fetuses) from May 2016 to December 2018.Using Trio-WES, we identified 32 disease-associated variants in 40 families (80% positive rate), which were subsequently verified. Known Mendelian diseases were identified in 12 families (30%), highly suspected Mendelian diseases in 12 families (30%), variants with uncertain significance in 8 families (20%), and no noticeable variants for 8 families (20%). Further analysis showed variants in 22 genes may cause fetal malformations. Four gene variants were detected in fetuses for the first time, which expanded the spectrum of the disease phenotype. Two novel candidate genes may be related to fetal malformations. Of 26 couples receiving PGD on diseaseassociated genes, 3 healthy newborns were delivered, and 4 couples are undergoing pregnancies. We reported the fetal data and developed an optimized genetic testing strategy. Our finding strongly suggests the presence of single gene Mendelian disorders in 60% of those families, and PGD services for couples to have healthy babies.

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International Cooperation to Enable the Diagnosis of All Rare Genetic Diseases

Cited by 354 publications

References 61 publications

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

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

Genomics for paediatricians: promises and pitfalls

Trio‐whole‐exome sequencing and preimplantation genetic diagnosis for unexplained recurrent fetal malformations

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