Pathogenic variants in SOX11 mimicking Pitt‐Hopkins syndrome phenotype

• Published in: Clinical genetics 2024-01, Vol.105 (1), p.81-86
• Main Authors: Pasquetti, Domizia, L'Erario, Federica Francesca, Marangi, Giuseppe, Panfili, Arianna, Chiurazzi, Pietro, Sonnini, Elena, Orteschi, Daniela, Alfieri, Paolo, Morleo, Manuela, Nigro, Vincenzo, Zollino, Marcella
• Format: Article
• Language: English
• Subjects: Autonomic nervous system; Child; Congenital defects; Facies; Female; Haploinsufficiency; Humans; Hypertrichosis; Hyperventilation - diagnosis; Hyperventilation - genetics; Intellectual disabilities; Intellectual Disability - diagnosis; Intellectual Disability - genetics; Intellectual Disability - pathology; Microencephaly; Neurodevelopmental disorders; Phenotype; Phenotypes; Pitt‐Hopkins syndrome; SOX11; SOXC Transcription Factors - genetics; Transcription Factor 4 - genetics; whole exome sequencing
• ISSN: 0009-9163; 1399-0004
• DOI: 10.1111/cge.14414

Pitt‐Hopkins syndrome (PTHS) is a rare neurodevelopmental disorder characterised by severe intellectual disability (ID), distinctive facial features and autonomic nervous system dysfunction, caused by TCF4 haploinsufficiency. We clinically diagnosed with PTHS a 14 6/12‐year‐old female, who had a normal status of TCF4. The pathogenic c.667del (p.Asp223MetfsTer45) variant in SOX11 was identified through whole exome sequencing (WES). SOX11 variants were initially reported to cause Coffin‐Siris syndrome (CSS), characterised by growth restriction, moderate ID, coarse face, hypertrichosis and hypoplastic nails. However, recent studies have provided evidence that they give rise to a distinct neurodevelopmental disorder. To date, SOX11 variants are associated with a variable phenotype, which has been described to resemble CSS in some cases, but never PTHS. By reviewing both clinically and genetically 32 out of 82 subjects reported in the literature with SOX11 variants, for whom detailed information are provided, we found that 7/32 (22%) had a clinical presentation overlapping PTHS. Furthermore, we made a confirmation that overall SOX11 abnormalities feature a distinctive disorder characterised by severe ID, high incidence of microcephaly and low frequency of congenital malformations. Purpose of the present report is to enhance the role of clinical genetics in assessing the individual diagnosis after WES results. On the top of the graphical percentage of SOX11‐patients and individual clinical manifestations are shown. Comparison of the most distinctive clinical signs of patients with mutations in SOX11, ARID1B and TCF4, respectively, is shown on the bottom, along with a representation of the overlapping phenotypes.