Co‐occurrence of Aicardi–Goutières syndrome type 6 and dyschromatosis symmetrica hereditaria due to compound heterozygous pathogenic variants in ADAR1 : a case series from India

Abstract

Aicardi-Gouti eres syndrome type 6 (AGS6) and dyschromatosis symmetrica hereditaria (DSH) are allelic disorders caused respectively by biallelic and heterozygous pathogenic variants in ADAR1. We report three unrelated children presenting with features of both AGS6 and DSH, two of whom had compound heterozygous pathogenic variants in ADAR1. We also describe the novel genetic variants in our cases and review the literature on association of ADAR1-related AGS6 and DSH with these phenotypes.

Multi-dimensional insight into the coexistence of pathogenic genes for ADAR1 and TSC2: careful consideration is essential for interpretation of ADAR1 variants

“…[40] About the substitution of amino acids p.Gly1007Arg caused by the variant c.3019G > A, according to the structural and functional prediction and plasmid expressing p.Gly1007Arg study, Rice et al considered that it had the dominant-negative effect, which inhibited the function of wild type protein by binding more tightly to dsRNA. [12] In the past reports, ADAR1-related AGS6 inherited through autosomal recessive inheritance, were manifested as acute onset of severe generalized dystonia of limbs, developmental regression or further aggravated developmental retardation and loss of previously acquired developmental skills, both secondary to febrile illness [11,14,15,41]. Other highly correlated symptoms also included microcephalus [11,14], nystagmus [14], bilateral striatal necrosis [11,14,15], intracranial calci cations [14,15], leukodystrophy [14,15], tremor [11,15] and stiffness [11,15].…”

“…[12] In the past reports, ADAR1-related AGS6 inherited through autosomal recessive inheritance, were manifested as acute onset of severe generalized dystonia of limbs, developmental regression or further aggravated developmental retardation and loss of previously acquired developmental skills, both secondary to febrile illness [11,14,15,41]. Other highly correlated symptoms also included microcephalus [11,14], nystagmus [14], bilateral striatal necrosis [11,14,15], intracranial calci cations [14,15], leukodystrophy [14,15], tremor [11,15] and stiffness [11,15]. Valve calci cation as a rare symptom also had been reported [27], however, this view needs to be questioned due to the lack of other relevant reports.…”

“…[11,15] Both the patients of c.3019G > A related AGS and autosomal recessive AGS6 could undergo a completely normal developmental or mild to moderate global developmental delay stage before the acute attack. [15] Differently, c.3019G > A related AGS were accompanied by typical DSH rash, while autosomal recessive AGS6 accompanied by typical DSH rash was relatively rare [3,12,14,15,41]. Autosomal recessive AGS6 onset in the rst year of life mostly, by contrast, c.3019G > A related AGS could onset relatively late.…”

“…[12] As a kind of pigmentary genodermatosis, DSH is characterized mixture of hyperpigmented and hypopigmented macules. [13] The condition of AGS combined DSH has been reported [14], however most patients with AGS6 wouldn't develop rash lesions typical of DSH. [12,15] Tuberous sclerosis complex (TSC), as an autosomal dominant disease, contributes to the dysfunction of the mammalian target of the rapamycin (mTOR) pathway resulting from pathogenic variants in TSC1 and TSC2 genes [16].…”

Case Report: Aicardi-Goutières Syndrome Type 6 and Dyschromatosis Symmetrica Hereditaria With Congenital Heart Disease and Mitral Valve Calcification – Phenotypic Variants Caused by Adenosine Deaminase Acting on the RNA 1 Gene Homozygous Mutations

“…They were all characterized by global developmental delay and dystonia, along with dyschromatosis of the extremities and facial freckling. Exome analysis performed for two patients both revealed compound heterozygous variants in ADAR1, while the third patient did not perform the genetic analysis ( 17 ).…”