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Alpha thalassemia‐X‐linked intellectual disability syndrome (ATR-X syndrome) is a well‐characterized X-linked recessive disorder caused by pathogenic variants in the ATRX gene, manifesting with intellectual disability, alpha-thalassemia, characteristic facial dysmorphism, genital anomalies and variable skeletal involvement. ClinGen classifies the ATRX–ATR-X syndrome association as Definitive, supported by reports of over 200 affected males carrying more than 190 distinct ATRX variants across at least nine unrelated families ([PMID:34524523]). Concordant segregation in multiplex pedigrees and consistent biochemical evidence of defective chromatin remodeling underpin this classification.
ATRX syndrome follows an X-linked recessive inheritance pattern. Segregation of hemizygous ATRX variants has been documented in 15 affected male relatives from nine multiplex families, with obligate carrier testing confirming skewed X-inactivation in female carriers ([PMID:21218045]). Genetic testing in cases with suggestive clinical features routinely identifies hemizygous variants in affected males and heterozygous carrier status in females.
A broad spectrum of ATRX variants underlies the syndrome, including missense changes clustering in the ADD (ATRX-Dnmt3-Dnmt3L) and SNF2 helicase domains, nonsense and frameshift changes, splice-site mutations, small deletions and rare deep intronic alleles. A recurrent missense variant, c.658T>C (p.Cys220Arg), exemplifies pathogenic disruption of the ADD domain ([PMID:21218045]). Over 190 germline ATRX mutations have now been catalogued, meeting the genetic evidence cap for a Definitive classification.
At the protein level, ATRX contains an N-terminal PHD-like zinc finger and a C-terminal SNF2-type ATPase domain. Functional studies demonstrate that the ADD domain specifically reads unmodified H3K4 and di- or trimethylated H3K9, directing ATRX to pericentromeric heterochromatin and telomeres in concert with HP1 ([PMID:21421568]; [PMID:21666677]). Mutations in either domain disrupt chromatin targeting, alter histone deposition, and impair neuronal gene regulation. A truncated mouse ATRX model lacking exon 2 (ATRXΔE2) exhibits reduced hippocampal long-term potentiation and contextual memory defects, mirroring the cognitive phenotype in patients ([PMID:20865721]). Earlier yeast two-hybrid work revealed ATRX’s interaction with the SET domain of EZH2, suggesting a role in transcriptional regulation via chromatin remodeling ([PMID:9499421]).
No credible conflicting evidence has emerged disputing ATRX’s role in ATR-X syndrome. Observed genotype–phenotype correlations indicate that missense and truncating mutations yield a spectrum of intellectual disability severity and hematologic involvement, but all patients share neurodevelopmental impairment.
In summary, ATRX pathogenic variants cause ATR-X syndrome through a loss-of-function mechanism affecting chromatin remodeling. Genetic testing for ATRX variants is indicated in males with intellectual disability and characteristic dysmorphic and hematologic findings. Identification of a pathogenic ATRX variant informs accurate diagnosis, genetic counseling, carrier testing in females, and anticipatory management of associated features.
Key Take-home: ATRX mutations lead to a definitive X-linked syndrome of intellectual disability and alpha-thalassemia via disrupted chromatin remodeling, guiding molecular diagnosis and family counseling.
Gene–Disease AssociationDefinitiveMore than 200 patients reported across >190 germline ATRX variants ([PMID:34524523]); consistent segregation in multiplex families; robust functional data Genetic EvidenceStrongX-linked recessive inheritance with >190 distinct pathogenic variants in over 200 male patients; segregation in nine families; reached ClinGen genetic evidence cap Functional EvidenceStrongADD and SNF2 domain studies show impaired chromatin binding and remodeling; mouse model exhibits hippocampal dysfunction; biochemical interaction with EZH2 confirms regulatory role |