SERPINF1 gene variants causing late-onset progressive deforming osteogenesis imperfecta - A study of 18 patients from India.

SERPINF1 gene variants lead to a severe type of osteogenesis imperfecta (OI) attributed to defects in the matrix mineralization. We present 18 patients with SERPINF1 gene variants leading to severe progressive deforming OI, the largest series in the world to date. These patients were normal at birth and had the first fracture between 2 months to 9 years; progression of deformities was seen in 12 adolescents who became nonambulatory. Radiologically, compression fractures with kyphoscoliosis, protrusio acetabuli, and lytic lesions in the metaphysis and pelvis were seen in older children with classical popcorn appearance in the distal femoral metaphysis in three. By exome sequencing and targeted sequencing, we identified ten variants. One was unreported and novel; three other novel variants in this series were reported earlier. The recurrent deletion inframe mutation p.phe277del was found in 5 patients from three families. Alkaline phosphatase was elevated in all children on the first visit. Bone mineral density was low in all patients and showed improvement at two years in seven children on regular pamidronate therapy. For others, the 2 year BMD data were not available. The Z scores for four of the seven children showed worsening at the 2-year follow-up.

Phenotypic variability of a TREX1 variant in Aicardi-Goutieres type 1 patients from the Indian subcontinent.

Aicardi-Goutieres Syndrome (AGS) is a heterogeneous genetic syndrome, manifesting early as encephalopathy and is associated with abnormal neurologic findings, hepatosplenomegaly, elevated liver enzymes, thrombocytopenia and intracranial calcification. The most severe neonatal type, AGS1, is caused by biallelic disease-causing variants in TREX1. In this study, we describe four patients with TREX1-related AGS1 whose phenotype overlaps with intra-uterine infections and neonatal lupus. Exome sequencing identified a previously reported TREX1 variant, c.223dup (NM_016381.5; p. Glu75GlyfsTer82) in all the four patients belonging to the Indian subcontinent. The functional consequence of the disease-causing variant was predicted by using a new combination of bioinformatics softwares. The recurrence of this pathogenic variant indicates a possible founder effect in TREX1 for AGS1 in this population. The phenotypic variability in those with this founder mutation can mimic intrauterine infections and neonatal lupus, thereby leading to misdiagnosis warranting a targeted genetic testing approach to be a part of the diagnostic workup to obtain a definite, early and cost-effective diagnosis in patients from Indian subcontinent with early onset encephalopathy.

Clinicogenetic Profile, Treatment Modalities, and Mortality Predictors of Gaucher Disease: A 15-Year Retrospective Study.

INTRODUCTION: Gaucher disease (GD) is a rare autosomal recessive lysosomal storage disorder, in which biallelic pathogenic variants in the Glucosidase beta acid (GBA) gene result in defective functioning of glucosylceramidase that causes deposition of glucocerebroside in cells. GD has 3 major types namely, non-neuronopathic (type I), acute neuronopathic (type II), and chronic neuronopathic (type III). Definite treatment options are limited and expensive. They succumb early to the disease, if untreated. There is paucity of studies from the Indian subcontinent, which elicit the factors resulting in their premature mortality. MATERIALS AND METHODS: A retrospective study was carried out in a tertiary care setting of South India to assess the clinical profile, mutation spectrum, and various management strategies (only supportive therapy, enzyme replacement therapy [ERT], substrate reduction therapy [SRT] haematopoietic stem cell transplant [HSCT]), and mortality predictors of patients with GD from 2004 to 2019. A Kaplan-Meier survival curve was plotted. In silico predictions were performed for novel variants. RESULTS: There were 60 patients with all types of GD seen over the study period of 15 years. Their median age at diagnosis was 2 years. The median follow-up was for 5 years (interquartile range [IQR] = 2-8). The overall mortality rate was 35%; however, it was only 10% in those receiving definite treatment. Mortality was higher (47.5%) by more than 4 folds in those only on supportive therapy. The median survival from the time of diagnosis was 6.3 years (IQR = 3.5-10.8) in the definite treatment group and 3.5 years (IQR = 1-5) in those on supportive therapy. The Kaplan-Meier survival analysis showed significant (p value 0.001) mortality difference between these groups. The multiple logistic regression analysis found the neuronopathic type (OR = 5) and only supportive therapy (OR = 6.3) to be the independent risk factors for premature mortality. CONCLUSION: GD is a rare disease with a high mortality rate, if left untreated. ERT and SRT are the definitive treatments which increase the survival. In resource-limited settings like India, with higher prevalence of the neuronopathic type, HSCT may be a more suitable definitive treatment option, due to its one-time intervention and cost, assuming similar efficacy to ERT. However, the efficacy and safety of HSCT in GD needs to be established further by substantial patient numbers undergoing it.

Alazami syndrome: Report of three Indian patients with phenotypic spectrum from adolescence to adulthood.

Alazami syndrome (ALAZS) (MIM 615071) is a rare autosomal recessive disorder characterized by short stature, dysmorphic facial features, developmental delay, and impaired intellect. It was first reported in a Saudi Arabian family in 2012. Three Indian patients affected with ALAZS, one boy aged 13 years and other two sisters in their 40s are presented. These patients had few unreported dysmorphic facial features: high arched eyebrows and dental overcrowding. No microcephaly was noted in the sisters. One of the sisters did not have short stature. The boy also presented with unilateral buphthalmos of left eye. All three of them have been identified to harbor novel variants in LARP7.