A 261 Kb Deletion Spanning Three Genes is Causing Rubinstein-Taybi Syndrome in a 6-Year-Old Boy Belonging to Kashmir Valley, India

Abstract

Rare diseases (RDs) are progressive, chronically debilitating and/or life-threatening heterogeneous clinical conditions that affect a limited fraction of individuals in comparison to other prevalent diseases. The World Health Organization (WHO) has established a basal prevalence rate of RDs of approximately 1 in 2,000 people. While there is no appropriate standard definition to describe a rare disease in India, Indian Council of Medical Research (ICMR) has defined a disease as rare if it affects less than 1 person in 2500 individuals. There are approximately 7000 rare diseases, and new ones are being published in the literature on a regular basis. In this article, we report a case of Rubinstein-Taybi syndrome type 1, a six-year-old boy (proband) belonging to Srinagar district of the Union Territory of Jammu and Kashmir (J&K), India established on the basis of phenotypic symptoms and radiological findings. Whole Exome Sequencing and further Comparative Genome hybridization confirmed the presence of a de novo copy number variation with a 261 kb heterozygous deletion present on 16 p13.3 cytoband (Chr16:3,694,760-3,955,374) (GRCh37) spanning three genes DNASE1 (OMIM #125505), TRAP1 (OMIM# 606219) and CREBBP (OMIM# 600140) in the proband only and missing in parents. Although microdeletions and deletions have been reported in CREBBP gene and adjacent genes but this is a novel deletion being reported for the first time in heterozygous state. Haploinsufficiency resulting from copy number loss, indicated by 0.78-fold decreased expression of the CREBBP gene in patient compared to parents is resulting in the development of the disease.

Note:
Funding declaration: Ankit Mahajan acknowledges Seed grant from University of Jammu reference no: Fin./2022-23/3246-52.

Conflict of Interests: The authors declare no competing interests

Ethical Approval: The family were included in the study after obtaining informed consent from the participants/their parents according to the Declaration of Helsinki. The study was approved (Approval No. RA/24/640) by the Institutional Ethical Committee at University of Jammu, Jammu.

Keywords: RDs: Rare Disease, RSTS: Rubinstein-Taybi syndromecGHS: Comparative Genomic HybridizationWHO: World Health OrganizationICMR: Indian Council of Medical ResearchWES: Whole Exome Sequencing CREBBP: cyclic-AMP response element binding binding prote