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Case Reports
. 2015 May;23(5):633-8.
doi: 10.1038/ejhg.2014.109. Epub 2014 Jun 11.

Missense variant in CCDC22 causes X-linked recessive intellectual disability with features of Ritscher-Schinzel/3C syndrome

Mateusz Kolanczyk  1 , Peter Krawitz  2 , Jochen Hecht  2 , Anna Hupalowska  3 , Marta Miaczynska  3 , Katrin Marschner  4 , Claire Schlack  4 , Denise Emmerich  1 , Karolina Kobus  4 , Uwe Kornak  4 , Peter N Robinson  4 , Barbara Plecko  5 , Gernot Grangl  6 , Sabine Uhrig  7 , Stefan Mundlos  8 , Denise Horn  4
Affiliations
Case Reports

Missense variant in CCDC22 causes X-linked recessive intellectual disability with features of Ritscher-Schinzel/3C syndrome

Mateusz Kolanczyk et al. Eur J Hum Genet. 2015 May.

Erratum in

Abstract

Ritscher-Schinzel syndrome (RSS)/3C (cranio-cerebro-cardiac) syndrome (OMIM#220210) is a rare and clinically heterogeneous developmental disorder characterized by intellectual disability, cerebellar brain malformations, congenital heart defects, and craniofacial abnormalities. A recent study of a Canadian cohort identified homozygous sequence variants in the KIAA0196 gene, which encodes the WASH complex subunit strumpellin, as a cause for a form of RSS/3C syndrome. We have searched for genetic causes of a phenotype similar to RSS/3C syndrome in an Austrian family with two affected sons. To search for disease-causing variants, whole-exome sequencing (WES) was performed on samples from two affected male children and their parents. Before WES, CGH array comparative genomic hybridization was applied. Validation of WES and segregation studies was done using routine Sanger sequencing. Exome sequencing detected a missense variant (c.1670A>G; p.(Tyr557Cys)) in exon 15 of the CCDC22 gene, which maps to chromosome Xp11.23. Western blots of immortalized lymphoblastoid cell lines (LCLs) from the affected individual showed decreased expression of CCDC22 and an increased expression of WASH1 but a normal expression of strumpellin and FAM21 in the patients cells. We identified a variant in CCDC22 gene as the cause of an X-linked phenotype similar to RSS/3C syndrome in the family described here. A hypomorphic variant in CCDC22 was previously reported in association with a familial case of syndromic X-linked intellectual disability, which shows phenotypic overlap with RSS/3C syndrome. Thus, different inactivating variants affecting CCDC22 are associated with a phenotype similar to RSS/3C syndrome.

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Figures

Figure 1
Figure 1
Facial photographs of patient 1 (a, b) and patient 2 (c, d) showing upslanting palpebral fissures, wide-set eyes, short philtrum, protruding tongue, and a broad neck. Hand anomalies of patient 1 (e, f) and patient 2 (g). Note camptodactyly, reduced distal creases of the second to fifth fingers, clinodactyly of the fifth fingers, and hypoplastic finger nails of the second to fifth fingers. Foot of patient 1 (h) showing a broad hallux and an overriding fifth toe.
Figure 2
Figure 2
A pedigree of the family affected by the CCDC22 variant. (a) Occurrence of the c.1670A>G variant in the family affected with RSS/3C syndrome. The CCDC22 genotypes are annotated below each tested family member. (b) Schematic representation of the CCDC22 protein structure with annotated functional domains and the location of the p.Y557C variant within the coiled-coil domain of the protein. (c) Evolutionary conservation of the mutated amino-acid residue in the CCDC22.
Figure 3
Figure 3
Western blot-based quantification of the CCDC22, strumpellin, Fam21, and Wash1 expression in the lymphoblastoid cell lines cells from affected patient, healthy mother, and non-related healthy control. Note a decreased expression of CCDC22 and increased expression of WASH1 in the patient cells. Statistical significance – t-test, *P≤0.05; **P≤0.01; ***P≤0.001.
Figure 4
Figure 4
Subcellular distribution of CCDC22 variants associated with RSS/3C spectrum disorders upon EGF uptake. HeLa cells were transfected either with WT, T17A, or Y557C Flag-tagged CCDC22 vectors and subjected to EGF uptake. Cells were immunostained for EEA1 (in red), Flag (in green), and EGF fluorescence is presented in blue. Scale bar=20 μm. The full colour version of this figure is available at European Journal of Human Genetics online.
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