Gene Variant Identification in A Malaysian Family with Underlying Heterotaxy Syndrome Using Whole Exome Sequencing (WES)

Ahmad Rafie, Nur Nabihah (2022) Gene Variant Identification in A Malaysian Family with Underlying Heterotaxy Syndrome Using Whole Exome Sequencing (WES). [Project Paper] (Submitted)

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Abstract

Heterotaxy syndrome (HTX) is a rare condition where the arrangement of the thoracoabdominal organs is abnormal, with a prevalence reported of 0.01% of the global population. Studies reported several gene variants that influence HTX. The variants reported were either sporadic or familial. To the best of our knowledge, no HTX genetic studies have been reported in Malaysian population. Objectives: This study aims to describe the clinical manifestation and inheritance pattern as well as to identify the presence of HTX related gene variants in the affected family members. Methodology: A six-membered family were recruited after obtaining informed consent, including the proband and her twin sisters who were diagnosed with HTX at Hospital Serdang. The patients’ clinical data were retrieved from medical records and family pedigree was constructed to observe the inheritance pattern. WES was performed using the DNA of the affected children. Reported variants were validated by Sanger sequencing on affected and unaffected family members. VCF files were further analyzed in-house based on the inheritance pattern (autosomal recessive), associated phenotypes and minor allele frequency (<0.01) using Galaxy Australia software to identify other possible variants in the patients. Results: All three affected daughters manifested right isomerism, dextrocardia, unbalanced atrioventricular septal defects and pulmonary atresia. WES diagnostic report showed two DNAH5 heterozygous variants (c.4556T>A, p.Ile1519Asn and c.9956T>G, p.Ile3319Ser) present in the affected patients. Sanger sequencing validated the presence of c.9956T>G heterozygous variant in the affected siblings, and their mother, while the father and son were homozygous wild type. However, c.4556T>A is absent in all family members. VCF files analysis revealed the affected siblings carrying heterozygous variant in MMP21 (c.818C>T, p.Thr273Met). Discussion: Patients’ clinical manifestations are consistent with previously reported right isomerism cases. It is postulated that trans-heterozygosity of DNAH5 c.9956T>G with MMP21 c.818C>T could be the cause of the syndrome development in the siblings. Previous studies had reported trans-heterozygosity involving interactions between variants in DNAH5 and other genes such as DNAH6, DNAH7 and DNAH11 in HTX. Conclusion: Patients’ clinical manifestations fit the description of previously reported HTX cases, and the condition is inherited in an autosomal recessive manner. This study suggests the syndrome occurs in the family likely due to he inheritance of trans-heterozygous variants of DNAH5 and MMP21. Further investigations are required to validate the presence of MMP21 c.818C>T variant in all family members, as well as the trans-heterozygosity of the DNAH5 and MMP21 variants.

Item Type:	Project Paper
Faculty:	Faculty of Medicine and Health Science
Depositing User:	Ms. Nor Safa'aton Saidin
Date Deposited:	22 Aug 2023 04:36
Last Modified:	22 Aug 2023 04:36
URI:	http://psaspb.upm.edu.my/id/eprint/1347

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