Widening of the genetic and clinical spectrum of Lamb–Shaffer syndrome, a neurodevelopmental disorder due to SOX5 haploinsufficiency

Purpose: Lamb–Shaffer syndrome (LAMSHF) is a neurodevelopmental disorderdescribed in just over two dozen patients with heterozygous genetic alterationsinvolving SOX5, a gene encoding atranscription factor regulating cell fate and differentiation in neurogenesisand other discrete developmental processes. The genetic alterations described sofar are mainly microdeletions. The present study was aimed at increasing ourunderstanding of LAMSHF, its clinical and genetic spectrum, and thepathophysiological mechanisms involved. Methods: Clinical and genetic data were collected through GeneMatcher andclinical or genetic networks for 41 novel patients harboring various types ofSOX5 alterations. Functional consequencesof selected substitutions were investigated. Results: Microdeletions and truncating variants occurred throughout SOX5. In contrast, most missense variants clusteredin the pivotal SOX-specific high-mobility-group domain. The latter variantsprevented SOX5 from binding DNA and promoting transactivation in vitro, whereasmissense variants located outside the high-mobility-group domain did not.Clinical manifestations and severity varied among patients. No cleargenotype–phenotype correlations were found, except that missense variantsoutside the high-mobility-group domain were generally better tolerated. Conclusions: This study extends the clinical and genetic spectrum associated withLAMSHF and consolidates evidence that SOX5haploinsufficiency leads to variable degrees of intellectual disability,language delay, and other clinical features.