De Novo SOX6 Variants Cause a Neurodevelopmental Syndrome Associated with ADHD, Craniosynostosis, and Osteochondromas.

SOX6 belongs to a family of 20 SRY-related HMG-box-containing (SOX) genes that encode transcription factors controlling cell fate and differentiation in many developmental and adult processes. For SOX6, these processes include, but are not limited to, neurogenesis and skeletogenesis. Variants in half of the SOX genes have been shown to cause severe developmental and adult syndromes, referred to as SOXopathies. We here provide evidence that SOX6 variants also cause a SOXopathy. Using clinical and genetic data, we identify 19 individuals harboring various types of SOX6 alterations and exhibiting developmental delay and/or intellectual disability; the individuals are from 17 unrelated families. Additional, inconstant features include attention-deficit/hyperactivity disorder (ADHD), autism, mild facial dysmorphism, craniosynostosis, and multiple osteochondromas. All variants are heterozygous. Fourteen are de novo, one is inherited from a mosaic father, and four offspring from two families have a paternally inherited variant. Intragenic microdeletions, balanced structural rearrangements, frameshifts, and nonsense variants are predicted to inactivate the SOX6 variant allele. Four missense variants occur in residues and protein regions highly conserved evolutionarily. These variants are not detected in the gnomAD control cohort, and the amino acid substitutions are predicted to be damaging. Two of these variants are located in the HMG domain and abolish SOX6 transcriptional activity in vitro. No clear genotype-phenotype correlations are found. Taken together, these findings concur that SOX6 haploinsufficiency leads to a neurodevelopmental SOXopathy that often includes ADHD and abnormal skeletal and other features.

Revisiting recombinant 8 syndrome.

Recombinant 8 syndrome, also known as San Luis Valley syndrome, is a rare but important cause for developmental delay and chronic illness noted among individuals of Hispanic ancestry that occurs with greater reported frequency in the Southwest United States. The recombinant chromosome is rec(8)dup(8q)inv(8)(p23.1q22.1) and in all known cases is derived by a parental pericentric inversion, inv(8)(p23.1q22.1). To test our hypothesis that modern medical management strategies may alter the outcome of patients with recombinant 8 syndrome in regard to mortality, morbidity, and neurodevelopmental outcomes, we sought to update the natural history of recombinant 8 syndrome by completing a thorough medical and psychological assessment of affected individuals. Twelve affected individuals, ranging from 2 to 21 years of age, were recruited with IRB approval. Our patients scored on in the mild to severe cognitive functioning level (range 30-70), with surprising preservation in the social/adaptive arenas. Most patients responded well to heart surgery and developmental outcomes were in proportion to cardiac status. Orthopedic surgery to ameliorate effects of spasticity can be complicated by long recovery times and decreased ability to ambulate. Our findings do not support additional morbidly during cardiac repair. Taken together, our findings support a consistent phenotype with improved survival in comparison to previously published studies. Efforts to encourage learning and developmental progress should not be withheld as quality of life for many of these individuals is considered good by their families and medical providers.