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

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-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_41delACA). 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 x 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 the first variant to be posited as a founder variant in the GLANS gene in patients with MPS IVA syndrome.

研究背景：粘多糖贮积症IVA型（Mucopolysaccharidosis IVA，又称莫基奥综合征A型，MPS IVA）是一种常染色体隐性溶酶体贮积症，由N-乙酰半乳糖胺-6-硫酸酯酶（N-acetylgalactoseamine-6-sulfatase, GALNS）基因的双等位基因变异引发。此前该疾病的突变谱已在印度北部、南部及东部人群中得到系统解析，但印度西部人群，尤其是古吉拉特印度裔群体，相关研究仍未开展。本研究旨在通过对23个无关家系患者的GALNS基因全部外显子及外显子-内含子边界进行测序，分析古吉拉特人群中GALNS基因的变异特征。研究结果：本研究共报道11种变异，包括8种错义变异：p.L36R、p.D39G、p.P77R、p.C79R、p.P125L、p.P151L、p.G255A及p.L350P；1种剪接位点变异：c.121-7C>G；1种小插入变异：c.1241_1242insA（对应蛋白变异为p.I416HfsTer2）；以及1种小缺失变异：c.839_41delACA。其中，3种错义变异（p.D39G、p.G255A及p.L350P）、1种剪接位点变异及上述2种插入缺失变异均为新发变异。值得注意的是，本研究队列中p.P77R变异的检出率高于预期（n=14/25，占比56%）。对携带p.P77R变异的患者及63名种族匹配的健康对照开展单倍型分析结果显示，与对照组相比，病例组存在由4个单核苷酸多态性（Single Nucleotide Polymorphism, SNP）组成的单倍型区块（似然比检验P值=1.16×10^-13），提示p.P77R变异为古吉拉特印度人群的奠基者变异。此外，突变年代分析显示该变异约于450年前在该人群中出现。研究结论：GALNS基因的p.P77R变异极有可能是古吉拉特印度裔MPS IVA患者的奠基者变异，该变异约于450年前在该人群中产生。据我们所知，这是首个在MPS IVA综合征患者中被提出为GALNS基因奠基者变异的位点。