Intellectual disability - microarray and sequencing
Gene: CCDC32The OMIM entry for this gene is OMIM:618941, which has been cross-checked with Ensembl, HGNC and G2P. Hence, gene-checked tag has been added.Created: 16 Oct 2023, 7:08 p.m. | Last Modified: 16 Oct 2023, 8:25 p.m.
Panel Version: 5.313
The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.Created: 30 Jan 2023, 5:50 p.m. | Last Modified: 30 Jan 2023, 5:50 p.m.
Panel Version: 4.53
Associated with relevant phenotype in OMIM and as strong Gen2Phen gene for CCDC32-associated neurodevelopmental syndrome. At least three variants have been reported in three unrelated cases (PMIDS: 32307552 & 35451546), together with supportive functional studies.Created: 25 Aug 2022, 3:10 p.m. | Last Modified: 25 Aug 2022, 3:10 p.m.
Panel Version: 3.1693
Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.Created: 25 Aug 2022, 3:07 p.m. | Last Modified: 25 Aug 2022, 3:07 p.m.
Panel Version: 3.1693
Biallelic pathogenic CCDC32 variants cause cardiofacioneurodevelopmental syndrome (# 619123).
There are 3 unrelated individuals with this disorder reported to date.
Common findings in all - summarized in Ref2 - included DD with speech delay, bilateral CLP, craniofacial features, cardiac defects and abnormalities of the fingers.
CCDC32 encodes a protein contributing to ciliary function [Ref1], providing explanation for some features reported in single individuals (e.g. heterotaxy). Depletion of ccdc32 in zebrafish recapitulated human phenotypes (microcephaly, midfacial defects, cerebellar hypoplasia) [Ref1]. Some additional evidence presented that the protein encoded binds AP2 and may have a role in clathrin-mediated endocytosis.
Please consider amber / green rating (given 2nd report) in the current panel and inclusion in other relevant ones (e.g. for cleft palate, heart defects, etc).
[1]-----
Harel et al (2020, PMID:32307552) described a 6 y.o. female, born to consanguineous parents. Her phenotype consisted of feeding difficulties, global DD, AV canal, abdominal situs inversus and asplenia, OFC at the 3rd-5th centile, cleft lip palate and additional facial features as well as skeletal findings (kyphosis, camptodactyly, clinodactyly). Ophthalmology, hearing and renal work-up were within normal limits. Following a normal CMA, WES revealed homozygosity for a frameshift CCDC32 variant as the only finding (NM_001080791.2:c.54dupT / p.Thr19Tyrfs*12) within a ROH of approx. 9 Mb. Sanger confirmed the variant, carrier status of the parents, compatible genotypes in unaffected sibs (htz/hmz wt), and homozygosity for the variant in an affected sib (cleft lip and additional prenatal findings).
Harel also reported a 3 y.o. male, born to 1st cousin parents, with bilaleral cleft lip, cleft palate, VSD and pulmonary valve stenosis. History was similar, with feeding difficulties, moderate motor and language delay, microcephaly, dysmorphic features, additional findings from limbs (clinodactyly, nail aplasia), and cryptorchidism. Ophthalmology examination (incl ERG) and renal US were normal. Exome revealed homozygosity for a fs insertion (c.189_190dupGG / p.Gly64Glyfs*12) within a 5.23 Mb ROH. There were no other relevant findings. The status of the proband and his parents was confirmed with Sanger s.
Both variants were absent from public databases.
CRISPR-Cas9-mediated ccdc32 depletion in zebrafish recapitulated the microcephaly (with normal body length), midfacial defects (CH angle) and cerebellar hypoplasia. The authors provided additional evidence that ccdc32 is required for embryonic axis development as depletion disrupted cardiac looping and impaired expression of a key L/R patterning transcript (southpaw). Cilia at the Kupffer's vesicle, an organizing center for L/R symmetry, were significantly reduced in number and length.
siRNA-mediated knockdown of Ccdc32 in mouse inner medullary collecting duct cells (mIMCD3) with GFP-labeled cilia, also revealed impairment of cilia formation.
Overall, the authors discuss that while the role of the encoded protein remains unknown, CCDC32 contributes to ciliary function (although some hallmark renal/polydactyly phenotypes were not observed).
[2]-----
Abdalla et al (2022 - PMID: 35451546) describe a 9 y.o. female born to consanguineous parents. Her phenotype consisted of ID, bilateral cleft lip and palate, short stature, bilateral conductive hearing loss, microcephaly and craniofacial and limb abnormalities (camptodactyly, clinodactyly, faint/absent interphalangeal creases), etc. Cardiac US revealed a MVP. The child also presented thrombocytopenia. Fundus examination and abdominal US were normal.
Trio exome sequencing with CNV analysis revealed a homozygous 32 kb deletion without other relevant findings. Homozygosity of the proband and carrier state of parents were confirmed by qPCR. Junction PCR revealed that the 5' breakpoint was within the intron 2 (common to all transcripts) and removed coding region and 3' UTR in most (7/8) transcripts (chr15:40529942-40562524 - hg38).
There was a similarly affected sib, unavailable for testing. Another sib with DD, epilepsy, sensorineural hearing impairment was heterozygous carrier of this deletion (suggesting a different cause for his disorder).
The authors cite a recent study (2021 - PMID: 33859415) suggesting that CCDC32 (previously: C15orf57) encodes a protein that binds the AP2 complex, localizing in clathrin-coated pits and playing a role in clathrin-mediated endocytosis of transferrin. Further they discuss similarities with disorders caused by mutations in genes encoding AP2 subunits and/or mouse models for AP2 subunit deficiencies (presenting cleft palate and cardiac defects).Created: 25 Apr 2022, 10:27 a.m. | Last Modified: 25 Apr 2022, 10:27 a.m.
Panel Version: 3.1561
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Cardiofacioneurodevelopmental syndrome (# 619123)
Publications
Comment on list classification: Rating amber as 2 cases plus some limited functional evidence. Rating agreed with Genomics England clinical team.Created: 23 Jul 2020, 3:51 p.m. | Last Modified: 23 Jul 2020, 3:51 p.m.
Panel Version: 3.177
PMID: 32307552 - Harel et al 2020 - report 2 unrelated consanguineous families with probands with homozygous frameshift variants in CCDC32. Parents are heterozygous. Phenotype is a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies. In one family the child had global developmental delay, in the other the child had moderately delayed motor and language development and hyperactivity.
Functional studies in zebrafish show that ccdc32 depletion impairs cilia formation and demonstrate a contribution of ccdc32 in craniofacial, brain and left/right axis development.
Sources: LiteratureCreated: 23 Jul 2020, 3:46 p.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
global developmental delay
Publications
Tag gene-checked tag was added to gene: CCDC32.
Tag watchlist was removed from gene: CCDC32. Tag Q3_22_rating was removed from gene: CCDC32.
Source NHS GMS was added to CCDC32. Source Expert Review Green was added to CCDC32. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Tag Q3_22_rating tag was added to gene: CCDC32.
Gene: ccdc32 has been classified as Amber List (Moderate Evidence).
Phenotypes for gene: CCDC32 were changed from global developmental delay to Cardiofacioneurodevelopmental syndrome, OMIM:619123; cardiofacioneurodevelopmental syndrome, MONDO:0030873
Publications for gene: CCDC32 were set to 32307552
Tag watchlist tag was added to gene: CCDC32.
Gene: ccdc32 has been classified as Amber List (Moderate Evidence).
gene: CCDC32 was added gene: CCDC32 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: CCDC32 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CCDC32 were set to 32307552 Phenotypes for gene: CCDC32 were set to global developmental delay Review for gene: CCDC32 was set to AMBER