RESUMEN
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.
Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad/genética , Craneosinostosis/genética , Trastornos del Neurodesarrollo/genética , Osteocondroma/genética , Factores de Transcripción SOXD/genética , Transporte Activo de Núcleo Celular , Adolescente , Secuencia de Aminoácidos , Secuencia de Bases , Encéfalo/embriología , Encéfalo/crecimiento & desarrollo , Encéfalo/metabolismo , Niño , Preescolar , Simulación por Computador , Femenino , Variación Estructural del Genoma/genética , Humanos , Lactante , Masculino , Mutación Missense , Trastornos del Neurodesarrollo/diagnóstico , RNA-Seq , Factores de Transcripción SOXD/química , Factores de Transcripción SOXD/metabolismo , Síndrome , Transcripción Genética , Transcriptoma , Translocación Genética/genéticaRESUMEN
BACKGROUND: Acellular dermal matrices (ADMs) are an integral component of breast reconstruction. The ideal matrix would be relatively immuno-inert, allow rapid vascularization, and be affordable. The purpose of this study was to histologically compare 2 commonly used ADM products. METHODS: This is a prospective histological study of 17 patients (20 breasts) following prosthetic-based breast reconstruction with ADM: Alloderm (LifeCell Corp, Branchburg, N.J.) or Cortiva (RTI Surgical, Alachua Fla.). Biopsies were taken from the dermal matrix and natural capsules surrounding the expander/implant during secondary surgery [Range, 72-694 days (mean, 217 days)]. Biopsy specimens were prepared via hematoxylin and eosin, Masson's trichrome, elastin, and transforming growth factor (TGF)-1 stains. Quantitative analysis of staining was performed with ImageJ software. The clinical outcome of each patient is analyzed in relation to capsule architecture and ADM performance. RESULTS: There were 7 breasts in the Alloderm group and 13 in the Cortiva group. Both groups had similar demographic, aesthetic results, and complication profiles. The TGF-1 staining demonstrated significantly lower levels in the Cortiva capsules (P = 0.0139). The percentage of elastin and collagen are similar in the Cortiva, Alloderm, and natural peri-implant capsules. The native capsules show a significantly greater number of blood vessels when compared with Cortiva and Alloderm (P = 0.0371 and P = 0.0347, respectively); however, there is no difference in vascular pattern between the 2 dermal matrices. DISCUSSION: Postoperatively, Cortiva demonstrates equal vascularity with less TGF-1 activation compared with Alloderm. The clinical success and complication profile were similar between the Alloderm and Cortiva patients.