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Deep Phenotyping of thirty-one cases of Aicardi-Goutières syndrome

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical- Pediatric
  • Secondary Categories:
    • Clinical- Pediatric
Introduction:
Aicardi-Goutières syndrome (AGS) is characterised as a type I interferonopathy and classically patients present in the neonatal period with features of congenital infection including microcephaly, hepatosplenomegaly, thrombocytopenia, irritability, seizures and intracranial calcification. Another cohort of patients presents later with global developmental delay, seizures, hypotonia, spasticity, chilblains and brain scan findings of cerebral atrophy, white matter signal hyperintensity and intracranial calcification. The literature also suggests there is variable expression, and some patients can also present with milder phenotype. AGS is most frequently inherited in an autosomal recessive manner with biallelic pathogenic variant in RNASEH2A, RNASEH2B, RNASEH2C, ADAR, SAMHD1, or TREX1; in a few instances the disease can result from specific de novo or inherited autosomal dominant pathogenic variants in TREX1 and IFIH1. Next generation sequencing technologies are enabling earlier diagnosis and identification of further disease-causing genes in individuals with AGS-like features. It is therefore important to further examine phenotypes associated with pathogenic variants of AGS-related genes, particularly in patients with milder phenotypes, who are being increasingly documented. We therefore studied the cohort of AGS cases with pathogenic variants from one centre (West Midlands) in England, United Kingdom.

Methods:
Patients were identified from the Clinical and molecular laboratory database and data was collected retrospectively for all patients. Retrospective case note review was performed from the electronic Clinical Genetics and Paediatric Neurology database. A standardised proforma was used to collect anonymised data which was pooled to analyse. Patients with a confirmed genetic diagnosis were included.

Results:
The study included 31 AGS patients (16 male, 15 female) aged from neonatal to 30 years. Eight patients were deceased. 21 patients were from consanguineous families. RNASEH2C mutations were most prevalent (55.2%). One case of fatal SAMHD1-related cerebrovascular disease was identified. 24 patients were homozygous, six compound heterozygous, and one heterozygous with a de novo variant. Most infants were born by natural conception (92%) with normal antenatal scans (68%). 84.6% were born term, 25% below or on the 0.4th weight centile, and eight had microcephaly. Majority (82%) were not dysmorphic. Neonatal complications included feeding difficulties (66.7%) and irritability (50.0%). Eight patients developed thrombocytopenia, six had hepatosplenomegaly, and seven showed neuroregression. Truncal hypotonia and peripheral hypertonia was seen in 17 patients. Seizures were documented in 17 patients: focal and clinical infantile spasms most prevalent. Only eight patients tolerated oral feeds, with thirteen on gastrostomy feeding. Hearing abnormalities were uncommon, and ophthalmological features were documented in 69.0% of patients. 15 patients had chilblains. Global developmental delay was seen in 89.3% (n=25) of patients, with three patients exhibiting mild or no delay. Eleven children were classified with severe learning difficulties, and 85.7% with varying severity overall. Three children had no learning difficulties. All patients underwent Magnetic Resonance Imaging (MRI), while 17 also had Computerised Tomography (CT) scans (16 showing calcification). MRI revealed white matter signal changes in 58.1%, brain atrophy in 61.3%, corpus callosal thinning in 38.7%, demyelination in 38.7%, and ventriculomegaly in 22.6%. Calcification was predominantly periventricular (66.7%). All patients tested showed raised interferon-alpha CSF levels (n=10).

Conclusion:
The study data is in keeping with the literature that AGS can present as a congenital infection like phenotype and can also manifest later with developmental delay, central hypotonia and spasticity. Autosomal recessive inheritance pattern is most common in our cohort and most common gene reported was RNASEH2C. Our data also showed the phenotypic variability of features with three children with normal intelligence, and striking intrafamilial heterogeneity was observed in sisters with identical RNASEH2C mutations: from normal cognitive function to severe disability. We propose study of large cohort of patients with AGS, particularly focusing on genotype-phenotype correlation studies, to improve prognostication and guide management.

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