No abstract

Given the genomic uniqueness, a local data set is most desired for Indians, who are underrepresented in existing public databases. We hypothesize patients with rare monogenic disorders and their family members can provide a reliable source of common variants in the population. Exome sequencing (ES) data from families with rare Mendelian disorders was aggregated from five centers in India. The dataset was refined by excluding related individuals and removing the disease‐causing variants (refined cohort). The efficiency of these data sets was assessed in a new set of 50 exomes against gnomAD and GenomeAsia. Our original cohort comprised 1455 individuals from 1203 families. The refined cohort had 836 unrelated individuals that retained 1,251,064 variants with 181,125 population‐specific and 489,618 common variants. The allele frequencies from our cohort helped to define 97,609 rare variants in gnomAD and 44,520 rare variants in GenomeAsia as common variants in our population. Our variant dataset provided an additional 1.7% and 0.1% efficiency for prioritizing heterozygous and homozygous variants respectively for rare monogenic disorders. We observed additional 19 genes/human knockouts. We list carrier frequency for 142 recessive disorders. This is a large and useful resource of exonic variants for Indians. Despite limitations, datasets from patients are efficient tools for variant prioritization in a resource‐limited setting.

The patatin-like protein family plays an important role in various biological functions including lipid homeostasis, cellular growth, and signaling. Conserved across species, the patatin domain is shared by all 9 members of the PNPLA family without redundancy in the coding sequences. The defective function of PNPLA2, PNPLA6, and PNPLA9 are known to cause mitochondrial-related neurodegeneration. Recently, PNPLA8 has been associated with mitochondrial myopathy and poor weight gain with lactic acidosis in 3 unrelated families. Using whole-exome sequencing, we identified a homozygous novel missense variation c.1874A>G in the patatin domain of PNPLA8. The patient had prenatal-onset severe and progressive neurodegeneration with mortality in infancy.

We report a boy with Eiken syndrome caused by a homozygous missense variant in Parathyroid hormone 1 receptor (PTH1R) c.103G > A [p.(Glu35Lys)]. Eiken syndrome is a very rare skeletal dysplasia due to bi-allelic variants in PTH1R. Only one affected family has been known to-date. The hallmarks include delayed ossification of bone including the epiphyses, pubic symphysis, and primary ossification centers of the short tubular bones, coarse bone trabeculae, and modeling abnormalities. The phenotype being described here recapitulates the delayed ossification and modeling abnormalities of Eiken syndrome. In addition, supernumerary epiphyses of the tubular bones of the hands and primary failure of eruption of teeth were observed in our proband. This report characterizes Eiken syndrome and confirms that bi-allelic hypomorphic variants in PTH1R are probably to cause this condition.

The phenotypic spectrum of Type 2 collagenopathies ranges from lethal achondrogenesis Type 2 to milder osteoarthritis with mild chondrodysplasia. All of them are monoallelic except for the two recent reports showing that biallelic variants in COL2A1 can cause spondyloepiphyseal dysplasia congenita in two children. Here we report two additional families with homozygous variants, c.4135C>T (p.Arg1379Cys) and c.3190C>T (p.Arg1133Cys) in COL2A1 resulting in two distinct skeletal dysplasia phenotypes of intermediate severity. Though all six patients from four families exhibit a spondylo‐epimetaphyseal dysplasia, they demonstrate a wide variation in severity of short stature and involvement of epiphyses, metaphyses, and vertebrae. We hypothesize that the variants are likely to be hypomorphic, given the underlying mechanisms of disease causation for known heterozygous variants in COL2A1. With this report, we provide further evidence to the existence of autosomal recessive Type 2 collagenopathy.

Overgrowth, defined as height and/or OFC ≥ +2SD, characterizes a subset of patients with syndromic intellectual disability (ID). Many of the disorders with overgrowth and ID (OGID) are rare and the full phenotypic and genotypic spectra have not been unraveled. This study was undertaken to characterize the phenotypic and genotypic profile of patients with OGID. Patients with OGID were ascertained from the cohort of patients who underwent cytogenetic microarray (CMA) and/or exome sequencing (ES) at our center over a period of 6 years. Thirty-one subjects (six females) formed the study group with ages between 3.5 months and 13 years. CMA identified pathogenic deletions in two patients. In another 11 patients, a disease causing variant was detected by ES. The spectrum of disorders encompassed aberrations in genes involved in the two main pathways associated with OGID. These were genes involved in epigenetic regulation like NSD1, NFIX, FOXP1, and those in the PI3K-AKT pathway like PTEN, AKT3, TSC2, PPP2R5D. Five novel pathogenic variants were added by this study. NSD1-related Sotos syndrome was the most common disorder, seen in five patients. A causative variant was identified in 61.5% of patients who underwent only ES compared to the low yield of 11.1% in the CMA group. The molecular etiology could be confirmed in 13 subjects with OGID giving a diagnostic yield of 42%. The major burden was formed by autosomal dominant monogenic disorders. Hence, ES maybe a better first-tier genomic test rather than CMA in OGID.

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The treatment for transfusion dependent thalassemia is costly and mostly borne by the families in India. This study provides a realistic magnitude of this burden and will be useful in planning a thalassemia management program at the state or national level.