Identification and functional analysis of novel SOX11 variants in Chinese patients with Coffin-Siris syndrome 9

Abstract

SOX11 is a transcription factor belonging to the sex determining region Y-related high-mobility group box family that plays a vital role in early embryogenesis and neurogenesis. De novo variants in SOX11 have been initially reported to cause a rare neurodevelopmental disorder, mainly referred to Coffin-siris syndrome 9 (CSS9, OMIM# 615866) which is characterized with growth deficiency, intellectual disability (ID), microcephaly, coarse facies, and hypoplastic nails of the fifth fingers and/or toes. A recent large-scale cohort study suggests that SOX11 variation would result in a clinically and molecularly distinct disease from CSS. Here, we describe three unrelated Chinese cases with variable phenotype, mainly involving developmental delay, ID, short statute, microcephaly, facial deformities (i.e., prominent forehead, arched eye brow, flat nasal bridge, broad nose and short philtrum), and cryptorchidism. Whole-exome sequencing (WES) revealed three novel heterozygous variants in the SOX11 gene, including two missense variants of c.337T>C (p.Y113H) and c.425C>G (p.A142G), and one nonsense variant of c.820A>T (p. K142*). Luciferase reporting assay shows that the two missense variants impair the transcriptional activity of the SOX11 target gene GDF5. Additionally, WES uncovered a 4,300 kb deletion involving the region of 1q24.2-q25.1 (hg19,chr1:169,433,149-173,827,682) in patient 1, which also contributes to the condition of the patient. In summary, this is the first report of Chinese cases with de novo variants of SOX11. Our study partially supports the previous observation that the phenotype caused by SOX11 variants somewhat differs from classical CSS.

Pathogenic variants in SOX11 mimicking Pitt‐Hopkins syndrome phenotype

“…Literature deals with a total of 82 subjects with pathogenic variants in SOX11 , including complete gene deletions (14%), missense (74%) and loss‐of‐function (12%) variants 4,5,7–19 . Detailed clinical information and clinical pictures were available for 32/82 subjects, including our patient.…”

Identification of a novel phenotype of external ear deformity related to Coffin–Siris syndrome‐9 and literature review

“…(2) Compared with prior CSS-9-related publications including nonsystematic literature review (Alburaiky et al, 2022;Al-Jawahiri et al, 2022;Diel et al, 2021;Ding et al, 2022;Hanker et al, 2022;Khan et al, 2018;Okamoto et al, 2018;Wakim et al, 2021), we did a systematic literature review in this study on reported CSS-9 cases and found that pathogenic SOX11 SNVs altering the HMG domain were more likely to cause the widest range of organ anomalies, reminding patients carrying those variants should be aware of potential risks of having multiple organ anomalies and need thorough clinical examination.…”

“…Since two SOX11 pathogenic SNVs were first identified by Tsurusaki et al (2014) to associate with CSS‐like phenotypes, many SOX11 pathogenic SNVs have been reported and the phenotypic spectrum of CSS‐9 has been further expanded (Alburaiky et al, 2022; Al‐Jawahiri et al, 2022; Cho et al, 2022; Diel et al, 2021; Ding et al, 2022; Hanker et al, 2022; Hempel et al, 2016; Khan et al, 2018; Okamoto et al, 2018; Tsurusaki et al, 2014; Wakim et al, 2021; Wang et al, 2023). Given the high variability of these phenotypes and multiple organ anomalies related to CSS‐9, it is obvious that CSS‐9 is an untypical subtype of CSS with increased heterogeneous phenotypes; new reports of CSS‐9 cases could identify further phenotypes related to this syndromic condition.…”

“…In the current study, we reported a CSS‐9 male exhibiting external ear malformation (microtia) with sensorineural deafness; this is the first report of external ear malformation caused by SOX11 SNVs, indicating that the SOX11 may play a potential role not only in inner ear development but also in external ear morphogenesis. (2) Compared with prior CSS‐9‐related publications including nonsystematic literature review (Alburaiky et al, 2022; Al‐Jawahiri et al, 2022; Diel et al, 2021; Ding et al, 2022; Hanker et al, 2022; Khan et al, 2018; Okamoto et al, 2018; Wakim et al, 2021), we did a systematic literature review in this study on reported CSS‐9 cases and found that pathogenic SOX11 SNVs altering the HMG domain were more likely to cause the widest range of organ anomalies, reminding patients carrying those variants should be aware of potential risks of having multiple organ anomalies and need thorough clinical examination.…”

“…On the other hand, 55 cases with intragenic SOX11 variants have been recorded (Alburaiky et al, 2022; Al‐Jawahiri et al, 2022; Cho et al, 2022; Diel et al, 2021; Ding et al, 2022; Hanker et al, 2022; Hempel et al, 2016; Khan et al, 2018; Okamoto et al, 2018; Tsurusaki et al, 2014; Wakim et al, 2021; Wang et al, 2023) so far, but no prior studies have provided a systematic summary or comprehensive overview on exploring relationships between intragenic SOX11 variants and phenotypic spectrum of organ anomalies in CSS‐9 cases.…”