Expansion of the CCDC22 associated Ritscher-Schinzel/3C syndrome and review of the literature: Should the minimal diagnostic criteria be revised?

Gjerulfsen, Cathrine E; Møller, Rikke S.; Fenger, Christina; Hammer, Trine Bjørg; Bayat, Allan

doi:10.1016/j.ejmg.2021.104246

Cited by 12 publications

(17 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A 16‐year‐old patient has been reported with similar facial and digital features without a posterior fossa malformation or CHD. He had a refractory epileptic encephalopathy (Gjerulfsen et al, 2021). While patient 1 was reported to have seizures, the history is unclear and without electrical correlation, and further cases will be needed to determine whether epilepsy is an uncommon manifestation of CCDC22‐ related RSS.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Delineating the CCDC22‐related Ritscher–Schinzel syndrome phenotype in the original family

Rodgers

Richmond

McGaughran

2022

American J of Med Genetics Pt A

View full text Add to dashboard Cite

Pathogenic variants in CCDC22 were initially described in 2012 in a large Australian family with intellectual disability and were subsequently noted to cause a phenotype consistent with the previously described Ritscher–Schinzel syndrome (RSS). The phenotypes of the original family were not described in detail and remains limited phenotypic data reported in medical literature. We detail the phenotypes of the original family, including newly diagnosed family members. With these eight phenotypic descriptions, more than triple the number of individuals for whom detailed clinical information is available. In addition to typical facies, common phenotypic features included intellectual disability, congenital heart disease and posterior fossa malformations, postnatal short stature, ectodermal abnormalities, and digital anomalies as previously described. Spinal curvature and genital anomalies were seen in most patients, while gastrointestinal features and disturbed sleep were also recurrently seen. We propose a possible mechanism linking the familial variant to a diagnosis of sarcoidosis in one individual. Given the clinical and genetic heterogeneity of RSS, we suggest a dyadic naming convention.

show abstract

Section: Discussionmentioning

confidence: 99%

“…This patient had refractory neonatal‐onset seizures despite multiple antiepileptic medications and a vagal nerve stimulator. This patient did not have congenital heart disease (CHD) or posterior fossa malformations (Gjerulfsen et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Delineating the CCDC22‐related Ritscher–Schinzel syndrome phenotype in the original family

Rodgers

Richmond

McGaughran

2022

American J of Med Genetics Pt A

View full text Add to dashboard Cite

show abstract

“…[4][5][6][7] In the SNX17-Retriever-CCC-WASH sorting pathway, WASHC4 has been reported as a causative gene for autosomal recessive intellectual disability (MIM615817), and CCDC22 and WASHC5 are known as responsible genes for Ritscher-Schinzel syndrome (RSS, MIM220210 and MIM300963), also known as 3C syndrome due to its triad of clinical features including craniofacial features, cerebellar anomalies and cardiac defects. [8][9][10][11][12] We previously reported siblings with biallelic loss-of-function variants in VPS35L, which is listed as the third responsible gene for RSS (MIM619135). The siblings showed overlapping phenotypes that were similar to 3C syndrome, including the triad of RSS, as well as global developmental delay, skeletal malformation and ophthalmological malformation.…”

Section: Phenotypesmentioning

confidence: 99%

Clinical diversity and molecular mechanism of VPS35L-associated Ritscher-Schinzel syndrome

et al. 2022

View full text Add to dashboard Cite

PurposeThe Retriever subunit VPS35L is the third responsible gene for Ritscher-Schinzel syndrome (RSS) after WASHC5 and CCDC22. To date, only one pair of siblings have been reported and their condition was significantly more severe than typical RSS. This study aimed to understand the clinical spectrum and underlying molecular mechanism in VPS35L-associated RSS. Methods We report three new patients with biallelic VPS35L variants. Biochemical and cellular analyses were performed to elucidate disease aetiology. Results. In addition to typical features of RSS, we confirmed hypercholesterolaemia, hypogammaglobulinaemia and intestinal lymphangiectasia as novel complications of VPS35Lassociated RSS. The latter two complications as well as proteinuria have not been reported in patients with CCDC22 and WASHC5 variants. One patient showed a severe phenotype and the other two were milder. Cells established from patients with the milder phenotypes showed relatively higher VPS35L protein expression. Cellular analysis found VPS35L ablation decreased the cell surface level of lipoprotein receptor-related protein 1 and low-density lipoprotein receptor, resulting in reduced low-density lipoprotein cellular uptake. Conclusion VPS35L-associated RSS is a distinct clinical entity with diverse phenotype and severity, with a possible molecular mechanism of hypercholesterolaemia. These findings provide new insight into the essential and distinctive role of Retriever in human development. HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY⇒ This study contributes to the establishment of a disease concept for VPS35L-associated RSS, and provides new insight into the essential and distinctive role of Retriever in human development.

show abstract

“…Several protein machineries are known to be essential for sequence-specific cargo transport including the well characterised Retromer complex, and the more recently identified Commander complex (2)(3)(4)(5). Commander regulates Retromerindependent endosomal retrieval and recycling of hundreds of proteins including integrins and lipoprotein receptors (6), and mutations in its subunits are causative for X-linked intellectual disability (XLID) and Ritscher-Schinzel syndrome (RSS), a multi-system developmental disorder characterised by craniofacial features, cerebellar hypoplasia, and stunted cardiovascular development (7)(8)(9)(10)(11)(12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

“…Other known transmembrane cargos such as the copper transporters ATP7A and ATP7B however, are trafficked via unknown mechanisms (30)(31)(32). As well as causing XLID and RSS developmental disorders, mutations in Commander subunits CCDC22 and VPS35L lead to hypercholesterolemia linked to reduced trafficking of LDLRs (7)(8)(9)(10)(12)(13)(14). The Commander complex is also required for cellular infection by human papilloma virus (HPV) (6), and CRISPR knockout screens have shown that Commander is essential for SARS-CoV-2 infection, potentially by regulating endosomal cholesterol homeostasis (33)(34)(35)(36).…”

Section: Introductionmentioning

confidence: 99%

Structure of the Commander endosomal trafficking complex linked to X-linked intellectual disability/Ritscher-Schinzel syndrome

Collins

McConville

Palmer

et al. 2023

Preprint

View full text Add to dashboard Cite

The Commander complex is required for endosomal recycling of diverse transmembrane cargos and is mutated in Ritscher-Schinzel syndrome. It comprises two subassemblies; Retriever composed of VPS35L, VPS26C and VPS29, and the CCC complex which contains ten subunits COMMD1-COMMD10 and two coiled-coil domain-containing (CCDC) proteins CCDC22 and CCDC93. Combining X-ray crystallography, electron cryomicroscopy and in silico predictions we have assembled a complete structural model of Commander. Retriever is distantly related to the endosomal Retromer complex but has unique features preventing the shared VPS29 subunit from interacting with Retromer-associated factors. The COMMD proteins form a distinctive hetero-decameric ring stabilised by extensive interactions with CCDC22 and CCDC93. These adopt a coiled-coil structure that connects the CCC and Retriever assemblies and recruits a sixteenth subunit, DENND10, to form the complete Commander complex. The structure allows mapping of disease-causing mutations and reveals the molecular features required for the function of this evolutionarily conserved trafficking machinery.

show abstract

Expansion of the CCDC22 associated Ritscher-Schinzel/3C syndrome and review of the literature: Should the minimal diagnostic criteria be revised?

Cited by 12 publications

References 23 publications

Delineating the CCDC22‐related Ritscher–Schinzel syndrome phenotype in the original family

Delineating the CCDC22‐related Ritscher–Schinzel syndrome phenotype in the original family

Clinical diversity and molecular mechanism of VPS35L-associated Ritscher-Schinzel syndrome

Structure of the Commander endosomal trafficking complex linked to X-linked intellectual disability/Ritscher-Schinzel syndrome

Contact Info

Product

Resources

About