TY - JOUR
T1 - Consolidation of the clinical and genetic definition of a SOX4- related neurodevelopmental syndrome
AU - Angelozzi, Marco
AU - Karvande, Anirudha
AU - Molin, Arnaud N.
AU - Ritter, Alyssa L.
AU - Leonard, Jacqueline M.M.
AU - Savatt, Juliann M.
AU - Douglass, Kristen
AU - Myers, Scott M.
AU - Grippa, Mina
AU - Tolchin, Dara
AU - Zackai, Elaine
AU - Donoghue, Sarah
AU - Hurst, Anna C.E.
AU - Descartes, Maria
AU - Smith, Kirstin
AU - Velasco, Danita
AU - Schmanski, Andrew
AU - Crunk, Amy
AU - Tokita, Mari J.
AU - De Lange, Iris M.
AU - Van Gassen, Koen
AU - Robinson, Hannah
AU - Guegan, Katie
AU - Suri, Mohnish
AU - Patel, Chirag
AU - Bournez, Marie
AU - Faivre, Laurence
AU - Tran-Mau-Them, Frédéric
AU - Baker, Janice
AU - Fabie, Noelle
AU - Weaver, K.
AU - Shillington, Amelle
AU - Hopkin, Robert J.
AU - Barge-Schaapveld, Daniela Q.C.M.
AU - Ruivenkamp, Claudia A.L.
AU - Bökenkamp, Regina
AU - Vergano, Samantha
AU - Seco Moro, Maria Noelia
AU - Díaz De Bustamante, Aranzazu
AU - Misra, Vinod K.
AU - Kennelly, Kelly
AU - Rogers, Caleb
AU - Friedman, Jennifer
AU - Wigby, Kristen M.
AU - Lenberg, Jerica
AU - Graziano, Claudio
AU - Ahrens-Nicklas, Rebecca C.
AU - Lefebvre, Veronique
N1 - Funding Information:
This work was funded by the Children’s Hospital of Philadelphia (VL and RAN), National Institute of Health NIAMS R01-AR68308 grant (VL), National Institute of Health NINDS K08-NS105865 grant (RAN) and National Institute of Health NIMH R01MH074090 and U01MH119705 grants (SMM). MB and LF are members of the European Reference Network for Developmental Anomalies and Intellectual Disability (ERN-ITHACA). Genome sequencing was funded for one patient by an internal grant from Children’s of Alabama and the HudsonAlpha Institute for Biotechnology Clinical Services Laboratory (ACEH, MD, KS). The inclusion of one patient was made possible through access to the France Genomic Medicine Plan 2025 database.
Publisher Copyright:
©
PY - 2022/3/1
Y1 - 2022/3/1
N2 - Background A neurodevelopmental syndrome was recently reported in four patients with SOX4 heterozygous missense variants in the high-mobility-group (HMG) DNA-binding domain. The present study aimed to consolidate clinical and genetic knowledge of this syndrome. Methods We newly identified 17 patients with SOX4 variants, predicted variant pathogenicity using in silico tests and in vitro functional assays and analysed the patients' phenotypes. Results All variants were novel, distinct and heterozygous. Seven HMG-domain missense and five stop-gain variants were classified as pathogenic or likely pathogenic variant (L/PV) as they precluded SOX4 transcriptional activity in vitro. Five HMG-domain and non-HMG-domain missense variants were classified as of uncertain significance (VUS) due to negative results from functional tests. When known, inheritance was de novo or from a mosaic unaffected or non-mosaic affected parent for patients with L/PV, and from a non-mosaic asymptomatic or affected parent for patients with VUS. All patients had neurodevelopmental, neurological and dysmorphic features, and at least one cardiovascular, ophthalmological, musculoskeletal or other somatic anomaly. Patients with L/PV were overall more affected than patients with VUS. They resembled patients with other neurodevelopmental diseases, including the SOX11-related and Coffin-Siris (CSS) syndromes, but lacked the most specific features of CSS. Conclusion These findings consolidate evidence of a fairly non-specific neurodevelopmental syndrome due to SOX4 haploinsufficiency in neurogenesis and multiple other developmental processes.
AB - Background A neurodevelopmental syndrome was recently reported in four patients with SOX4 heterozygous missense variants in the high-mobility-group (HMG) DNA-binding domain. The present study aimed to consolidate clinical and genetic knowledge of this syndrome. Methods We newly identified 17 patients with SOX4 variants, predicted variant pathogenicity using in silico tests and in vitro functional assays and analysed the patients' phenotypes. Results All variants were novel, distinct and heterozygous. Seven HMG-domain missense and five stop-gain variants were classified as pathogenic or likely pathogenic variant (L/PV) as they precluded SOX4 transcriptional activity in vitro. Five HMG-domain and non-HMG-domain missense variants were classified as of uncertain significance (VUS) due to negative results from functional tests. When known, inheritance was de novo or from a mosaic unaffected or non-mosaic affected parent for patients with L/PV, and from a non-mosaic asymptomatic or affected parent for patients with VUS. All patients had neurodevelopmental, neurological and dysmorphic features, and at least one cardiovascular, ophthalmological, musculoskeletal or other somatic anomaly. Patients with L/PV were overall more affected than patients with VUS. They resembled patients with other neurodevelopmental diseases, including the SOX11-related and Coffin-Siris (CSS) syndromes, but lacked the most specific features of CSS. Conclusion These findings consolidate evidence of a fairly non-specific neurodevelopmental syndrome due to SOX4 haploinsufficiency in neurogenesis and multiple other developmental processes.
KW - abnormalities
KW - congenital
KW - gene expression regulation
KW - genetic variation
KW - hereditary
KW - neonatal diseases
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U2 - 10.1136/jmedgenet-2021-108375
DO - 10.1136/jmedgenet-2021-108375
M3 - Article
C2 - 35232796
AN - SCOPUS:85133974753
SN - 0022-2593
VL - 59
SP - 1058
EP - 1068
JO - Journal of Medical Genetics
JF - Journal of Medical Genetics
IS - 11
ER -