Clinically relevant variants in Indian populations
We have analysed and compared pathogenic variants with ≥ 5 carrier frequency in genes related to different phenotypic classes: Inborn errors of metabolism, Maturity onset diabetes of the young (MODY), Cystic fibrosis and hereditary cancers.
Inborn errors of metabolism: We have compiled genes related to thyroid, carbohydrate, energy and amino acid IEM classes. Table – provides list of pathogenic variants in different IEM classes. Majority of these disorders are treatable. Therefore, inclusion of variants implicated in IEM disorders in genetic screening might benefit patients by early treatment or dietary interventions. In amino acid metabolism, a pathogenic variant (rs5742905) in cystathionine beta-synthase (CBS) gene is associated with homocystinuria. This variant has highest carrier frequency of 4% (f=0.04) in our cohorts while other databases doesn’t report any frequency for this variant. Frequency of another frequent variant (rs13078881) in BTD gene (f=0.03) is similar in our cohorts as well as SAS populations in other global databases. This variant is associated with Biotinidase deficiency whose partial deficiency is reported to be higher and is majorly asymptomatic in nature. In thyroid metabolism, a variant in SLC2A4 has frequency of 0.01% frequency in Clindb as well as SAS populations in other databases under study. This variant is associated with thyroid hypoplasia.
In carbohydrate metabolism, a variant (rs267606858) in GYG1 gene has frequency of 3% (frequency (f) = 0.03) in our cohorts while SAS populations in global resources reported has frequency of 0% Mutations in GYG1 are associated with glycogen storage disease XV disorders. Similarly, in energy metabolism, variant rs148639841 in ACAT1 gene has frequency of 0.04% (f=0.004) in Clindb while there is no representation from global populations.
  1. MODY: Maturity-onset diabetes of the young (MODY), one of the diseases inherited as an autosomal dominant trait. This form of diabetes is underrepresented either because of misdiagnosis or sometimes it remains undetected (Nair, Chapla, Arulappan, & Thomas, 2013). It has high prevalence rate in Asian Indians, is genetically heterogeneous and has many subtypes (Table 4). We screened 14 genes related to 14 MODY subtypes. We found three variants in GCK gene (Maturity-onset diabetes of the young, type 2) with our defined frequency criteria. These variants having frequency ranging from 0.0009-0.04 have frequency in our study with absence in global databases. Majority of the cases are known to be have either GCK or HNF1A mutation in European populations. However, a recent study highlighted that they observed GCK mutations in <1% of Indian patients and HNF1A is commonly mutated among patients (~7%) (Mohan et al., 2018). However, GCK mutations are more represented in our cohorts than reported earlier. It is possible that the earlier studies have been conducted on fewer samples. Equally possible is that the so-called pathogenic variants are non-consequential and does not necessarily need pharmacological intervention and therefore, remains underrepresented in patients.
  2. Cystic Fibrosis: We have prioritized 6 pathogenic variants from cystic fibrosis transmembrane conductance regulator (CFTR) gene. This included classical Cystic Fibrosis (CF) causing Phenylalanine 508 (F508) deletion (rs113993960, f=0.0016) which has ~70% frequency in CFTR2 database. It causes misfolding of CFTR and is known to be the most common cause of autosomal recessive Cystic Fibrosis (CF). Our analysis suggests that other variants in CFTR are as frequent as this classical deletion in our cohorts (f=0.001-0.002). Representation of these variants is either less or nearly absent in global databases expect rs193922500 (f=0.001-0.03 in SAS groups in global databases). The CFTR variants are also linked to other phenotypes. For example, pancreatic insufficiency, male infertility and sino-pulmonary disease. Heterogeneity in CFTR phenotypes depends upon the type of mutations in CFTR gene (Noone & Knowles, 2001). Mutations that doesn’t lead to complete loss of function has less severe phenotypes as compared to classical cystic fibrosis, where there is a complete loss of function of CFTR gene.
  3. Hereditary Cancers: On mapping 853 pathogenic genetic variants (in 99 cancer predisposing genes) from 33 cancer subtypes in 10,389 cases with our dataset, we retrieved set of 18variants (13 genes) in our study. Number of carriers in these variants’ ranges from n=1 to n=5, which is less than our described threshold. Number of carriers for variants in GJB2 (Deafness related) and CHEK2 (Familial cancer of breast) genes are 5 and 4 respectively. On mapping 99 cancer predisposing genes, we retrieved 26other pathogenic variants with high carrier frequency in ALK, Neuroblastoma (f=0.01), MAP2K2, multiple tumor types (f=0.007) and BRAC2, Breast-ovarian cancer, familial 2 (f=0.005) and GJB2, deafness related (f=0.005).
  4. Variants in gene related to other system disorders: the observed data of the monogenic disease related genes responsible for other critical organs, brain, heart etc (Table-2 ). Thus, it highlights the gap in the knowledge and their true occurrence of the genetically confirmed cases of various rare childhood and adult onset Mendelian disorders in Indian population. For instance, 133 heterozygous occurrences of 11 pathogenic variants in genes related to cardiac arrhythmias (Channelopathy genes, KCNH2 , KCNQ1 andSCN5A ), cardiomypathies (MYBPC3 and TNNT2 ) were observed. Seven variants with 145 heterozygous count in various muscular dystrophy genes; mainly in CAPN3 and SELENONwere observed. In addition multiple heterozygous calls were observed in the genes linked to various syndromic, neurological, renal and hemoglobinpathies disorders. Thus this frequency data of multiple rare pathogenic variants necessitates the relevant identification of patients carrying such defects in clinics and also allow appropriate mutation centric approach for rapid diagnosis.