2018 Fiscal Year Annual Research Report
Investigation of novel genes responsible for intellectual disability and multiple congenital anomalies of unknown etiology
| Project/Area Number |
17K17693
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
ウエハラ ダニエラチアキ 東京医科歯科大学, 難治疾患研究所, 特任助教 (90779513)
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| Project Period (FY) |
2017-04-01 – 2019-03-31
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| Keywords | Intellectual disability / Congenital anomalies / Sequencing / Candidate gene |
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| Outline of Annual Research Achievements |
Aiming at discovering novel genes responsible for undiagnosed intellectual disability and multiple congenital anomalies (ID/MCA), parent-child whole-exome sequencing was performed in six probands previously negative for pathogenic copy number variations or single nucleotide variants in 61 known ID/MCA genes.
A causative or candidate gene could be detected in three cases (50%), in which one is a known ID/MCA gene and two are novel candidate genes: (1) A de novo missense variant (p.Ile80Thr) in GNB1 was detected in a case with severe ID and hypotonia. De novo GNB1 mutations are the cause of a known ID syndrome (mental retardation autosomal dominant 42). (2) An extremely rare missense variant in an X-linked gene encoding a deubiquitinating enzyme was identified in a male patient with severe development delay. This variant was inherited from the unaffected mother, who has a completely skewed X inactivation. Through GeneMatcher, we established a collaboration with a group from the National Human Genome Research Institute of the U.S. National Institutes of Health. Functional studies have revealed that the variant detected in our patient causes protein mislocalization, leading to an impaired deubiquinating process. (3) A de novo missense variant in a kinetochore gene was detected in a patient born with intra-uterine growth retardation (IUGR) and microcephaly. Functional studies to correlate the mutation to IUGR/microcephaly are currently ongoing. No causative gene could be detected in the three remaining cases.
In conclusion, we were able to identify two novel candidate genes.
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