Further evidence of affected females with a heterozygous variant in FGF13 causing X-linked developmental and epileptic encephalopathy 90.

Developmental and epileptic encephalopathies (DEE) are a genetically heterogeneous group of disorders characterised by early onset epilepsy, epileptiform activity on electroencephalogram and associated developmental delay or neuroregression. With the advent of high throughput sequencing, novel gene-disease associations have been described for DEEs. Voltage activated sodium channels (Nav) regulate neuronal excitability. Fibroblast growth factor homologous factors (FHFs) are proteins, which bind to the C terminal cytoplasmic tails of alpha subunits of Nav channels and influence their function and surface expression. Gain of function hemizygous or heterozygous variants in FGF13 (also known as FHF2) were recently identified as the cause for X-linked developmental and epileptic encephalopathy 90 (DEE90; MIM# 301058) in seven individuals from five families, which included one female. We report an additional female, providing further evidence for a novel de novo heterozygous missense variant in FGF13, NM_004114.5: c.14T > G p.(Ile5Ser) causing X-linked DEE90. In addition, we review the genotype and phenotype of affected individuals with DEE90.

Multilocus disease-causing genomic variations for Mendelian disorders: role of systematic phenotyping and implications on genetic counselling.

Multilocus disease-causing genomic variations (MGVs) and multiple genetic diagnoses (MGDs) are increasingly being recognised in individuals and families with Mendelian disorders. This can be mainly attributed to the widespread use of genomic tests for the evaluation of these disorders. We conducted a retrospective study of families evaluated over the last 6 years at our centre to identify families with MGVs and MGDs. MGVs were observed in fourteen families. We observed five different consequences: (i) individuals with MGVs presenting as blended phenotypes (ii) individuals with MGVs presenting with distinct phenotypes (iii) individuals with MGVs with age-dependent penetrance (iv) individuals with MGVs with one phenotype obscured by another more predominant phenotype (v) two distinct phenotypes in different individuals in families with MGVs. Consanguinity was present in eight (8/14, 57.1%) of them. Thirteen families had two Mendelian disorders and one had three Mendelian disorders. The risk of recurrence of one or more conditions in these families ranged from 25% to 75%. Our findings underline the importance of the role of a clinical geneticist in systematic phenotyping, challenges in genetic counselling and risk estimation in families with MGVs and MGDs, especially in highly inbred populations.

p.Arg69Trp in RNASEH2C is a founder variant in three Indian families with Aicardi-Goutières syndrome.

Aicardi-Goutières syndrome is an early-onset severe neurological disorder characterized by intracranial calcification, white matter abnormalities, hepatosplenomegaly, cerebrospinal fluid lymphocytosis, and elevated interferon-α levels, thus mimicking congenital viral infections. It is a genetically heterogeneous condition and autosomal recessive and autosomal dominant forms with variations in seven genes known till date. Variations in RNASEH2C cause an autosomal recessive form of AGS. Here we report three Indian families with variant, c.205C>T (NM_032193.3, p.Arg69Trp) in RNASEH2C gene identified by whole-exome sequencing and targeted molecular testing of the variant. Review of literature and our data suggest this is likely to be a founder variant in Asians and it would be a good initial variant to screen in patients with Aicardi-Goutières syndrome in Indians.

Novel mutation in an Indian patient with Methylmalonic Acidemia, cblA type.

We report on a girl with methylmalonic acidemia, cblA type with a novel homozygous mutation and describe the clinical phenotype and response to therapy.