ATRX – Intellectual Disability–Hypotonic Facies Syndrome, X-Linked, 1

ATRX-related intellectual disability–hypotonic facies syndrome, X-linked, 1 is an X-linked recessive disorder characterized by global developmental delay, language impairment, hypotonia and distinctive facial features. In a 3-year-old boy presenting with profound developmental delay and mild craniofacial dysmorphism, whole-genome sequencing identified a novel hemizygous intronic ATRX variant, c.5786+4A>G, that segregates with disease and leads to skipping of exon 24 (PMID:35444965). The carrier mother exhibited extreme skewing of X-chromosome inactivation, supporting pathogenicity. To date, only a single unrelated proband with this phenotype–genotype correlation has been described, placing the gene–disease association in the Limited category based on one proband and segregation evidence.

Functional workup including RT-PCR confirmed aberrant splicing and exon exclusion, consistent with loss of ATRX chromatin-remodeling function (PMID:35444965). While ATRX dysfunction is well established in alpha-thalassemia–mental retardation syndromes, this case expands the phenotypic spectrum to isolated intellectual disability without hemoglobinopathy. Additional experimental validation and larger case series are required to upgrade the clinical validity. Key Take-home: Identification of c.5786+4A>G in ATRX informs genetic diagnosis, carrier testing and prenatal counseling in families at risk.

References

• Frontiers in Pediatrics | 2022 | Identification of a Hemizygous Novel Splicing Variant in ATRX Gene: A Case Report and Literature Review. PMID:35444965

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