2017 Fiscal Year Research-status 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 |
The aim of this research is to discover novel genes responsible for undiagnosed intellectual disability and multiple congenital anomalies (ID/MCA) using next-generation sequencing in eight probands previously negative for genomic rearrangements.
In a prior investigation we conducted in FY2017, 105 patients presenting with ID/MCA were subjected to a screening of single nucleotide variants by targeted resequencing using a 75-gene custom panel, in which 61 genes are the most frequently mutated known genes causing ID/MCA and 14 are candidate genes. Likely causative variants in known genes were found in 20% of the cases (21/105), whereas only one variant (of uncertain significance) was detected in a candidate gene.
So far, trio whole-exome sequencing has been performed in three patients that were negative for pathogenic mutations in the previous step. In one of them, we detected a maternally-inherited X-linked variant in a male proband. Since the variant is predicted to be damaging to the protein function and the mutated gene has not been associated to any human disorder to date, it might be a novel candidate for ID/MCA. In order to confirm the pathogenicity of this mutation, we are currently planning functional experiments to check a possible deleterious effect. Bioinformatics analysis of exome data of the other two patients is currently ongoing.
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| Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
The original research plan had the goal of identifying novel candidate genes responsible for ID/MCA of unknown etiology, which intended to be achieved as follows:
(i) whole-exome sequencing of 10 parent-child trios: due to budget restrictions, we changed the number of parent-child trios to eight. So far, we have performed experiments in three families.
(ii) data analysis with a focus on de novo variants, X-linked maternally inherited variants in male probands, and compound heterozygous variants: the ongoing analysis has already suggested a potential X-linked novel candidate gene.
(iii) functional studies for the characterization of novel candidate genes: this step is being currently carried out for the X-linked gene mentioned above.
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| Strategy for Future Research Activity |
Besides the detailed investigation on the significance of the candidate variants found in the three patients already analyzed, in this fiscal year our plan is as follows: (i) to perform trio whole-exome sequencing in additional five patients, also negative for pathogenic variants after the targeted resequencing screening; (ii) to perform functional studies for the extensive characterization of novel candidate genes by in silico, in vitro and in vivo analysis; (iii) to report the outcome of the research in peer-reviewed scientific journals and in domestic/international scientific meetings.
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