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. 2022 Jun 21;23(1):458.
doi: 10.1186/s12864-022-08693-4.

The GALNS p.P77R variant is a probable Gujarati-Indian founder mutation causing Mucopolysaccharidosis IVA syndrome

Harsh Sheth  1 , Premal Naik  2 , Maulin Shah  3 , Riddhi Bhavsar  4 , Aadhira Nair  4 , Frenny Sheth  4 , Jayesh Sheth  5
Affiliations

The GALNS p.P77R variant is a probable Gujarati-Indian founder mutation causing Mucopolysaccharidosis IVA syndrome

Harsh Sheth et al. BMC Genomics. .

Abstract

Background: Mucopolysaccharidosis IVA (Morquio syndrome A, MPS IVA) is an autosomal recessive lysosomal storage disorder caused due to biallelic variants in the N-acetylgalactoseamine-6-sulfate sulfatase (GALNS) gene. The mutation spectrum in this condition is determined amongst sub-populations belonging to the north, south and east India geography, however, sub-populations of west Indian origin, especially Gujarati-Indians, are yet to be studied. We aimed to analyse the variants present in the GLANS gene amongst the population of Gujarat by sequencing all exons and exon-intron boundaries of the GALNS gene in patients from 23 unrelated families.

Results: We report 11 variants that include eight missense variants: (p.L36R, p.D39G, p.P77R, p.C79R, pP125L, p.P151L, p.G255A and p.L350P), one splice site variant: (c.121-7C > G), one small insertion: (c.1241_1242insA, p.I416HfsTer2) and one small deletion: (c.839_841delACA). Of these, three missense variants (p.D39G, p.G255A and p.L350P), one splice site and the two indels mentioned above are novel. Interestingly, we observed a higher than anticipated prevalence of p.P77R variant in our cohort (n = 14/25, 56%). Haplotype analysis in cases with p.P77R variant and 63 ethnicity matched healthy population controls suggested a 4 SNP haplotype block present in cases compared to controls (likelihood ratio test p-value = 1.16 × 10-13), thereby suggesting p.P77R variant as a founder variant in the Gujarati-Indian population. Furthermore, age of mutation analysis suggested the variant to have arisen approximately 450 years ago in the population.

Conclusion: p.P77R variant in the GLANS gene is likely to be a founder variant in MPS IVA patients of Gujarati-Indian ancestry and appeared approximately 450 years ago in the population. To our knowledge, this is the first variant to be posited as a founder variant in the GLANS gene in patients with MPS IVA syndrome.

Keywords: Founder variant; GALNS; Morquio A syndrome; Mucopolysaccharidosis IVA (MPS IVA); p.P77R.

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Conflict of interest statement

The authors declare that they have no conflict of interests.

Figures

Fig. 1
Fig. 1
Schematic representation of the variants identified in the GALNS gene in patients with MPS IVA from India to date. Variants highlighted in red are observed in the present study whereas variants highlighted in blue are reported by Bidchol et al. 2014 [12] and the present study. Variants highlighted in green has reported in the Chinese population and the present study
Fig. 2
Fig. 2
Linkage disequilibrium, haplotype and age of variant analysis for p.P77R variant in the GALNS gene in Gujarati-Indian population. Linkage disequilibrium plot in A 63 controls B 13 cases with p.P77R variant in the GALNS gene. Red colour intensity represents strength of linkage disequilibrium (measured in R2) between 2 SNPs. C Predicted age of variant plot generated by the DMLE software. Green indicates values within 95% confidence intervals
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