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.
- 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.
- 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.
- 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).
- 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.