Carrier frequency of SMN1-related spinal muscular atrophy in north Indian population: The need for population based screening program.

Chromosome 5q related Spinal muscular atrophy (SMA) is an autosomal recessive, progressive, neuromuscular disorder most commonly caused by homozygous deletion of exon 7 or exon 7 and 8 of SMN1 gene. Being the leading genetic cause of infant mortality, studies of its prevalence and incidence are necessary. Carrier testing for the common pathogenic variant for SMA is offered to the couples visiting our tertiary care hospital in North India. Subjects were tested for SMA carrier status by Multiplex Ligation-dependent Probe amplification (MLPA) technique for deletion of exons 7 and 8 of SMN1 gene. The retrospective data of individuals tested for SMA carrier status in last 4 years (2016-2019) was evaluated. Six hundred and six individuals without family history of SMA or carrier of SMA who were subjected to MLPA based screening for SMA carrier status were included in the study. The carrier frequency of SMN1 deletion (deletion of exon 7 and/or exon 8) was found to be 1 in 38 (16 out of 606). The catchment area of our medical genetics clinic covering the state of Uttar Pradesh (16.5% of Indian population according to censusindia.gov.in, 2011) and neighboring states, showing SMA carrier frequency of 1:38 in a cohort with no prior positive family history has important significance for policy making.

Progressive Pseudorheumatoid Dysplasia of Childhood (PPRD)-A Case Series with Recurrent c.740_741del Variant.

Progressive pseudorheumatoid dysplasia (PPRD) is an autosomal recessive arthropathy, affecting school-aged children. It is characterized by progressive degeneration of the articular cartilage. The majority of the pathogenic variations are found in exon 2, exon 4, and exon 5 of the putative gene, CCN6 (WISP3). Three unrelated individuals with clinical diagnosis of PPD were included in this study. Detailed clinicoradiological evaluation was attempted with brief literature review. Exome sequencing was performed in all three cases. All the pathogenic variations detected in our cohort were located in exons 2 and 4 of WISP3 gene. Though the clinicoradiological features are already well described, this study in north India highlights the occurrence of a recurring pathogenic variant. The c.740_741del variant was a recurrent pathogenic variant seen in all three patients in this cohort. This may be a common pathogenic variant in the North Indian population; however, a larger cohort needs to be studied before drawing final conclusions. A proper molecular diagnosis is a must to end the diagnostic odyssey, safeguarding patients with PPRD from unnecessary use of drugs like corticosteroids.

Variable neurological phenotypes of homocystinuria caused by biallelic methylenetetrahydrofolate reductase variants.

Inherited methylenetetrahydrofolate reductase (MTHFR) deficiency is associated with a wide spectrum of disorders including homocystinuria. This study aims to describe the neurological phenotypes and molecular profiles of patients with homocystinuria caused by biallelic variants in MTHFR. We report six subjects with MTHFR deficiency who presented with variable neurological phenotypes which could be viewed as a continuous spectrum. Fatal infantile encephalopathy was observed in one family, whereas another patient presented at 27 years with acute leukoencephalopathy and recovered within 3 months. Intermediate forms presenting as complicated hereditary spastic paraparesis of variable severity were observed in four subjects. Clinical and molecular information of the 207 cases reported in literature were also retrieved and analyzed. We categorized all subjects into three categories - severe, intermediate and mild forms according to the clinical presentation. In addition, a total of 286 disease-causing variations reported to date were analyzed. These included seven disease-causing variants reported in this study of which one is novel. Some genotype-phenotype correlation could be seen which corroborated with previous observations. However, inter- and intrafamilial variability was also noted. Treatment with betaine, B12 and folic acid was started in four subjects with variable outcomes.

Deciphering the molecular landscape of microcephaly in 87 Indian families by exome sequencing.

Microcephaly is a frequent feature of neurodevelopmental disorders (NDDs). Our study presents the heterogeneous spectrum of genetic disorders in patients with microcephaly either in isolated form or in association with other neurological and extra-neural abnormalities. We present data of 91 patients from 87 unrelated families referred to our clinic during 2016-2020 and provide a comprehensive clinical and genetic landscape in the studied cohort. Molecular diagnosis using exome sequencing was made in 45 families giving a yield of 51.7%. In 9 additional families probable causative variants were detected. We identified disease causing variations in 49 genes that are involved in different functional pathways Among these, 36 had an autosomal recessive pattern, 8 had an autosomal dominant pattern (all inherited de novo), and 5 had an X-linked pattern. In 41 probands where sequence variations in autosomal recessive genes were identified 31 were homozygotes (including 16 from non-consanguineous families). The study added 28 novel pathogenic/likely pathogenic variations. The study also calls attention to phenotypic variability and expansion in spectrum as well as uncovers genes where microcephaly is not reported previously or is a rare finding. We here report phenotypes associated with the genes for ultra-rare NDDs with microcephaly namely ATRIP, MINPP1, PNPLA8, AIMP2, ANKLE2, NCAPD2 and TRIT1.

Novel pathogenic variants in an Indian cohort with epidermolysis bullosa: Expanding the genotypic spectrum.

BACKGROUND: Epidermolysis bullosa (EB) is a genodermatosis characterized by skin fragility and blisters with variable severity. Patients with Dystrophic EB (DEB) or Junctional EB (JEB) mainly present to clinic due to greater functional impairment. Pathogenic sequence variations in COL7A1 are implicated in DEB. OBJECTIVE: We have tried to decipher the molecular spectrum and genotype phenotype correlation of 21 Indian patients with EB. METHODS: Next generation sequencing (NGS) was performed to determine the pathogenic variants. Sanger sequencing was also done for validation of the variants in eleven individuals. RESULTS: Pathogenic variants were detected in 20 individuals (diagnostic yield of 95%). Majority of them (90%) had sequence variation in COL7A1 while two had pathogenic variants in ITGB4 and KRT14 respectively. Out of the 18 patients confirmed to have DEB, 3 had Dominant DEB (DDEB) whereas 15 patients had Recessive DEB (RDEB). Amongst 23 sequence variations identified, 12 were found to be novel (3 were missense, 5 were premature termination codon variants while 4 were splice-site changes). CONCLUSION: Genotype phenotype correlation was noted with milder manifestations in those with dominant inheritance types. Exact molecular diagnosis can be ascertained by NGS in majority of cases.

Partial Trisomy of Chromosome 8q and Partial Monosomy of Chromosome 6p with Robinow Syndrome-Like Phenotype.

Genetic disorders can be monogenic or chromosomal. Deletions, duplications, and cryptic imbalances due to rearrangements of the telomeres are seen in a number of patients with psychomotor and language delay. Here, the authors report a case of 1-y-old boy born to nonconsanguineous couple who was evaluated for global developmental delay with phenotypic resemblance to a monogenic disorder namely Robinow syndrome. Cytogenetic microarray showed a double segment imbalance involving chromosome 6p25.3p25.2 and chromosome 8q23.3q24.3. Robinow syndrome also known as fetal face syndrome is a rare disorder with characteristic facial phenotype resembling fetal face with macrocephaly, low-set ears, broad great toes, gum hypertrophy, micropenis, and rhizomelia. Facial features include hypertelorism, wide mouth and short nose with upturned tip. It can have dominant or recessive mode of inheritance. The chromosomal abnormality in this case may provide clue to some novel gene for Robinow syndrome etiology.

Pearson Syndrome: Spontaneously Recovering Anemia and Hypoparathyroidism.

Pearson syndrome is a genetic disorder caused by mutations in the mitochondrial genome, characterized by failure to thrive with hematological and gastrointestinal abnormalities. Individuals with Pearson syndrome may develop the symptoms and signs of Kearns-Sayre syndrome with multisystem involvement. Spontaneous recovery of hematological problems is reported as is the situation in the present case. The child reported here was born out of in-vitro fertilization. She was maintaining normal hemoglobin level for more than three and a half years but had been detected to have hypoparathyroidism. The diagnosis of Pearson syndrome was confirmed by presence of deletion in mitochondrial genome. Awareness about this rare disorder will help clinicians to broaden their differentials when dealing with common presentations like failure to thrive and anemia.