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Suleiman-El-Hattab syndrome is a rare autosomal recessive multisystem developmental disorder caused by biallelic loss-of-function variants in TASP1. To date, eight probands from six unrelated families have been reported with homozygous or compound heterozygous splice, frameshift, and nonsense variants, confirming autosomal recessive inheritance (PMID:37474017, PMID:35512351). No additional affected relatives segregating variants have been described.
The variant spectrum includes canonical splice-site c.404-2A>G, recurrent frameshift c.314_315del (p.Ser105Ter), nonsense variants c.199C>T (p.Arg67Ter), and missense changes p.Met120Ile and p.Thr234Met, reflecting loss of taspase 1 function.
Patients uniformly present with global developmental delay, intellectual disability, distinctive facial features, and a characteristic happy demeanor. Additional features reported include cystic hygroma, increased nuchal thickness, coarctation of the aorta, pulmonary stenosis, chronic constipation, encephalomalacia, and aggressive behavior (PMID:37474017).
Functional studies demonstrate absence of TASP1 protein by Western blot, downregulation of HOX genes (HOXA1, HOXA4, HOXA7, HOXB2), and TFIIA dysregulation in patient fibroblasts. Methylome analyses reveal an intermediate profile between controls and Kabuki syndrome. Zebrafish tasp1 knock-out models exhibit reduced head size and cranial cartilage defects, recapitulating human phenotypes (PMID:35512351).
No studies have refuted the association. The cumulative genetic and experimental evidence meets criteria for a strong gene-disease association.
Key Take-home: Molecular testing for biallelic TASP1 variants is recommended for individuals with developmental delay, happy disposition, and multisystem anomalies to confirm Suleiman-El-Hattab syndrome.
Gene–Disease AssociationStrongEight probands from six unrelated families with biallelic loss-of-function TASP1 variants and concordant functional data Genetic EvidenceStrongEight independent probands across six families harboring homozygous or compound heterozygous splice, frameshift, and nonsense variants Functional EvidenceModerateZebrafish tasp1 knock-out replicates craniofacial defects; patient fibroblasts show absence of TASP1, HOX dysregulation and a distinct methylation signature |