Abstract: PO1645
Whole-Exome Sequencing Identifies Likely Causative Variants in Four Candidate Genes in 16 Families with Spina Bifida
Session Information
- Genetic Diseases of the Kidneys: Non-Cystic - 2
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1002 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Wang, Chunyan, Boston Children's Hospital, Boston, Massachusetts, United States
- Wu, Chen-Han Wilfred, Boston Children's Hospital, Boston, Massachusetts, United States
- Seltzsam, Steve, Boston Children's Hospital, Boston, Massachusetts, United States
- Zheng, Bixia, Boston Children's Hospital, Boston, Massachusetts, United States
- Schneider, Sophia, Boston Children's Hospital, Boston, Massachusetts, United States
- Schierbaum, Luca M., Boston Children's Hospital, Boston, Massachusetts, United States
- Mann, Nina, Boston Children's Hospital, Boston, Massachusetts, United States
- Nakayama, Makiko, Boston Children's Hospital, Boston, Massachusetts, United States
- Shril, Shirlee, Boston Children's Hospital, Boston, Massachusetts, United States
- Bauer, Stuart B., Boston Children's Hospital, Boston, Massachusetts, United States
- Baum, Michelle Amy, Boston Children's Hospital, Boston, Massachusetts, United States
- Estrada, Carlos R., Boston Children's Hospital, Boston, Massachusetts, United States
- Hildebrandt, Friedhelm, Boston Children's Hospital, Boston, Massachusetts, United States
Group or Team Name
- Boston Children's Hospital
Background
Spina bifida (SB) is the most common central nervous system malformation compatible with life and the second leading cause of birth defects. The following lines of evidence support the hypothesis that SB may be caused by multiple monogenic genes: i) congenital nature, ii) familial occurrence, and iii) existence of monogenic mouse models. However, only few monogenic genes have been described so far and the majority of the candidate genes derived from mouse models have not been studied in human SB.
Methods
We evaluated the literature and generated a list of 95 candidate genes from four categories: i) 7 known genes from human isolated SB, ii) 11 genes from human syndromic SB, iii) 35 genes considered risk factors for human SB, and iv) 42 genes from monogenic mouse models for SB. We evaluated whole exome sequencing (WES) data obtained from 16 individuals with SB who were enrolled at Boston Children’s Hospital from 06/2019 to 11/2019.
Results
In 4 of 16 families (25%), we identified 4 likely deleterious heterozygous (het) mutations in each one potential SB candidate gene. All variants are very rare with a frequency of less than 0.01% in a control database of 125,000 healthy control individuals (gnomAD). Specifically, in family B4103 with myelomeningocele, we identified a CELSR1 het missense mutation (c.2296G>A; p.Asp766Asn). In family B4197 with myelomeningocele, we identified a TBXT het missense mutation (c.301C>T; p.Arg101Cys). In family B4125 with meningocele, we found a het missense mutation in the human risk SB gene PCYT1A (c.194A>G; p.Glu65Gly). Finally, in the family B4197 with SB, we identified a het missense mutation in the mouse SB gene TULP3 (c.703C>T; p.Asp766Asn). TULP3 variants have not been reported yet in human SB patients.
Conclusion
Through whole exome sequencing, we detected likely deleterious mutations in 4 of 16 cases with a diagnosis of SB. We show that composing a list of 95 candidate genes based on established mouse models and genes known to be related to SB in human facilitates the detection of monogenic causes for SB. We are expanding this study to a larger cohort.