A 1-y-old male child, the second offspring of second-degree consanguineous parents, was referred for evaluation of early infantile-onset neuroregression. He was born at term gestation and there were no adverse events in the antenatal, perinatal and neonatal periods. He had plateauing of developmental milestones by 3 mo of age, followed by regression of the initially attained social smile and partial head control. There was no history of seizures or other systemic symptoms. On examination, the child had macrocephaly (head circumference: 52 cm; +4.3 SD), with weight of 8.4 kg (−1.9 SD), and length of 74 cm (−0.55 SD). Other than frontal prominence and deep-set eyes, no other significant dysmorphic features were noted (Fig. 1A). Nervous system examination revealed head lag, lack of eye contact, normal response to sounds, spastic quadriparesis, brisk deep tendon reflexes, bilateral upgoing plantar reflex, and absence of involuntary movements. No significant findings were noted on cardiovascular, respiratory and abdominal examination. Magnetic resonance imaging (MRI) of the brain (done with a 3 Tesla MRI machine) showed symmetrical white matter hypo-intensities in T1 and hyperintensities in T2 with partial suppression on FLAIR sequences involving the subcortical white matter of bilateral frontal, parietal and anterior temporal lobes with frontal predominance. Mild ventricular prominence was also noted (Fig. 1B). MR spectroscopy (MRS) of the brain was normal. Gas chromatography mass spectrometry (GCMS) of urine, complete ophthalmology evaluation and hearing evaluation were normal. Whole exome sequencing revealed a homozygous novel missense variant c.724T>C (p.Tyr242His) in exon 4 of the GFAP gene (ENST00000588735.3). The variant was classified as ‘likely pathogenic’ (PP3 + PM1 + PM5 + PM2) as per the variant classification guidelines of the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP). Targeted Sanger sequencing of the variant confirmed homozygosity of the variant in the child and heterozygous carrier status in both the asymptomatic parents. The variant was absent in his asymptomatic elder sibling (Fig. 1C). Genetic counseling of the parents was done, and symptomatic and supportive care was advised for the child. Clinical examination of the parents, including detailed central nervous system evaluation, was unremarkable for both. MRI brain was suggested for both parents, but as they were asymptomatic, they did not wish to opt for it. Both parents have been advised to come for annual follow-up or earlier in case of appearance of any neurological symptoms.

(A) Clinical photograph of the child showing macrocephaly, frontal prominence, and deep-set eyes. (B) MRI Brain showing symmetric bilateral frontal, parietal, and anterior temporal subcortical white matter T1 hypo-intensities (B1) and T2 hyperintensities (B2), with partial suppression on FLAIR (B3), along with bilateral ventricular prominence (white matter changes have been marked out with arrows). (C) Targeted Sanger sequencing of GFAP gene showing homozygosity of the variant c.724T>C in the proband (C1), absence of the variant in the asymptomatic elder sibling (C2), and heterozygous carrier status in both the asymptomatic parents (C3 & C4)