Cochlear nerve deficiency in <scp><i>SOX11</i></scp>‐related <scp>Coffin‐Siris</scp> syndrome

Alburaiky, Salam; Taylor, Juliet; O’Grady, Gina L.; Thomson, Glen D.; Perry, David J.; England, Eleina; Yap, Patrick

doi:10.1002/ajmg.a.62851

Cited by 6 publications

(8 citation statements)

References 39 publications

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“…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.…”

Section: Resultsmentioning

confidence: 99%

Pathogenic variants in SOX11 mimicking Pitt‐Hopkins syndrome phenotype

Pasquetti,

L'Erario,

Marangi

et al. 2023

Clinical Genetics

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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.

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Section: Resultsmentioning

confidence: 99%

Pathogenic variants in SOX11 mimicking Pitt‐Hopkins syndrome phenotype

Pasquetti,

L'Erario,

Marangi

et al. 2023

Clinical Genetics

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“…(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.…”

Section: Discussionmentioning

confidence: 99%

“…Among these CSS subtypes, CSS‐9 (OMIM#615866) is caused by heterozygous deficiency in the SRY‐related HMG‐box 11 ( SOX11 ) gene on 2p25.2, which is an expression regulation gene that encoded an important functional domain, high‐mobility group (HMG) box, and involved in the process of chromatin remodeling (Tsurusaki et al, 2014). CSS‐9 patients have been found to have cleft palate, hearing loss (including conductive and sensorineural subtypes), inner ear malformation (such as cochlear hypoplasia), ophthalmic, and genitourinary abnormalities in recent years (Alburaiky et al, 2022; Diel et al, 2021; Khan et al, 2018; Neirijnck et al, 2018; Wang et al, 2023), and the phenotypic spectrum of CSS‐9 has been expanded further (Al‐Jawahiri et al, 2022), but no studies thus far have documented the external ear malformation caused by SOX11 deficiency.…”

Section: Introductionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Wu,

Tang,

et al. 2024

American J of Med Genetics Pt A

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De novo germline variants of the SRY‐related HMG‐box 11 gene (SOX11) have been reported to cause Coffin–Siris syndrome‐9 (CSS‐9), a rare congenital disorder associated with multiple organ malformations, including ear anomalies. Previous clinical and animal studies have found that intragenic pathogenic variant or haploinsufficiency in the SOX11 gene could cause inner ear malformation, but no studies to date have documented the external ear malformation caused by SOX11 deficiency. Here, we reported a Chinese male with unilateral microtia and bilateral sensorineural deafness who showed CSS‐like manifestations, including dysmorphic facial features, impaired neurodevelopment, and fingers/toes malformations. Using trio‐based whole‐exome sequencing, a de novo missense variant in SOX11 (NM_003108.4: c.347A>G, p.Y116C) was identified and classified as pathogenic variant as per American College of Medical Genetics guidelines. Moreover, a systematic search of the literature yielded 12 publications that provided data of 55 SOX11 intragenic variants affecting various protein‐coding regions of SOX11 protein. By quantitatively analyzing phenotypic spectrum information related to these 56 SOX11 variants (including our case), we found variants affecting different regions of SOX11 protein (high‐mobility group [HMG] domain and non‐HMG regions) appear to influence the phenotypic spectrum of organ malformations in CSS‐9; variants altering the HMG domain were more likely to cause the widest range of organ anomalies. In summary, this is the first report of CSS with external ear malformation caused by pathogenic variant in SOX11, indicating that the SOX11 gene may be not only essential for the development of the inner ear but also critical for the morphogenesis of the external ear. In addition, thorough clinical examination is recommended for patients who carry pathogenic SOX11 variants that affect the HMG domain, as these variants may cause the widest range of organ anomalies underlying this condition.

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“…50 Nevertheless, there may still be genetic determinants that underlie these 2 origins. For example, CND has been reported in patients with CHARGE, VACTERL, and Coffin-Siris syndromes, [51][52][53] which are hereditary and associated with USNHL. 54 Furthermore, multiple genes have been documented involved in inner ear malformations in syndromic and nonsyndromic SNHL.…”

Section: Discussionmentioning

confidence: 99%

Genetic Underpinnings and Audiological Characteristics in Children With Unilateral Sensorineural Hearing Loss

Lee

Lin

Chiang

et al. 2023

Otolaryngol.--head neck surg.

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ObjectiveUnilateral sensorineural hearing loss (USNHL) is a condition commonly encountered in otolaryngology clinics. However, its molecular pathogenesis remains unclear. This study aimed to investigate the genetic underpinnings of childhood USNHL and analyze the associated audiological features.Study DesignRetrospective analysis of a prospectively recruited cohort.SettingTertiary referral center.MethodsWe enrolled 38 children with USNHL between January 1, 2018, and December 31, 2021, and performed physical, audiological, imaging, and congenital cytomegalovirus (cCMV) examinations as well as genetic testing using next‐generation sequencing (NGS) targeting 30 deafness genes. The audiological results were compared across different etiologies.ResultsCausative genetic variants were identified in 8 (21.1%) patients, including 5 with GJB2 variants, 2 with PAX3 variants, and 1 with the EDNRB variant. GJB2 variants were found to be associated with mild‐to‐moderate USNHL in various audiogram configurations, whereas PAX3 and EDNRB variants were associated with profound USNHL in flat audiogram configurations. In addition, whole‐genome sequencing and extended NGS targeting 213 deafness genes were performed in 2 multiplex families compatible with autosomal recessive inheritance; yet no definite causative variants were identified. Cochlear nerve deficiency and cCMV infection were observed in 9 and 2, respectively, patients without definite genetic diagnoses.ConclusionGenetic underpinnings can contribute to approximately 20% of childhood USNHL, and different genotypes are associated with various audiological features. These findings highlight the utility of genetic examinations in guiding the diagnosis, counseling, and treatment of USNHL in children.

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Cochlear nerve deficiency in SOX11‐related Coffin‐Siris syndrome

Cited by 6 publications

References 39 publications

Pathogenic variants in SOX11 mimicking Pitt‐Hopkins syndrome phenotype

Pathogenic variants in SOX11 mimicking Pitt‐Hopkins syndrome phenotype

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

Genetic Underpinnings and Audiological Characteristics in Children With Unilateral Sensorineural Hearing Loss

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