CCNQ

Gene Facts

• HGNC Symbol: CCNQ (HGNC:28434)
• HGNC Name: cyclin Q
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: FAM58A
• Alias symbols: CycM
• %HI: 61.79
• pLI: 0.9
• LOEUF: 0.4
• Cytoband: Xq28
• Genomic Coordinates:

  GRCh37/hg19:	chrX:152853383-152864595
  GRCh38/hg38:	chrX:153587925-153599139

• MANE Select Transcript: NM_152274.5 ENST00000576892.8
• Function: Activating cyclin for the cyclin-associated kinase CDK10. {ECO:0000269|PubMed:18297069, ECO:0000269|PubMed:24218572}. (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-21217
• ClinGen Curation ID: CCID:006804
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Emerging Evidence for Haploinsufficiency (2)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 12/01/2021

Haploinsufficiency (HI) Score Details

• HI Score: 2
• HI Evidence Strength: Emerging Evidence for Haploinsufficiency

HI Disease

• syndactyly-telecanthus-anogenital and renal malformations syndrome

HI Evidence

• PUBMED: 18297069
  Unger et al. (2008) describe CCNQ pathogenic loss-of-function variants in four unrelated girls with a consistent constellation of facial dysmorphism, toe syndactyly, telecanthus and anogenital and renal malformations (STAR syndrome). One individual was found to have a de novo 40 kb deletion removing the coding regions of exons 1 and 2 as well as intron 1, a portion of intron 2, and the 5' UTR of the CCNQ gene. Another was found to have a de novo heterozygous 4,249 bp deletion which removed 1,265 bp of intron 4, all of exon 5, including the 3' UTR, and 2,454 bp of 3' sequence. The remaining individuals were found to have point variants, including a de novo frameshift variant 201dupT, which results in a premature stop codon (Asn68TerfsTer1), and a c.555+1G>A splice donor site variant, and a c.556-1G>A splice acceptor site variant (inherited from an affected mother). None of the variants were seen in the DNA of 60 unaffected female controls, and no larger deletions involving CCNQ were found in 93 unrelated array-CGH investigations.
• PUBMED: 28322501
  Boczek et al (2017) reported a pathogenic nonsense variant, c.651G>A (p.Trp217X; NM_152274) in an 8-year-old female with STAR syndrome and the variants co-segregated with another two affected individuals in this family. The proband's mother and maternal half-sister had similar clinical histories, but had variability in phenotypic severity.
• PUBMED: 26882209
  Orge et al. (2015) presented a mother-daughter pair with X-linked dominant STAR syndrome with a 65 kilobase deletion of chromosome Xq28 encompassing the 5′ end of the CCNQ gene affecting its regulatory region. The mother had a much more mild presentation of STAR syndrome compared to her daughter with respect to syndactyly, anogenital and renal malformations, and ophthalmic findings.
• PUBMED: 29088509
  Bedeschi et al. (2017) reported a female patient with STAR syndrome and a 130 kb deletion at Xq28, including the CCNQ gene. She presented with cleft lip palate, omphalocele, and cerebral malformations not previously considered part of the phenotypic spectrum of this syndrome. She died at 6 weeks from respiratory failure. Excluded since the deletion includes three OMIM genes (CCNQ, DUSP9, and PNCK) and disrupts the ATPB23 gene
• PUBMED: 28225384
  Lefroy et al. (2017) identified a 107 kb heterozygous deletion of the entire CCNQ gene and ATP2B3 gene [arrXq28(152 788 477–152 895 818)×1] in a 19-year-old woman with STAR syndrome. Her mother, who had only bilateral 4-5 toe syndactyly, was found to have approximately 50% mosaicism for the same deletion. Excluded since the deletion includes both the CCNQ and the ATPB23 gene.
• PUBMED: 25845904
  Zarate et al (2015) reported a heterozygous genomic loss of 232 kb at Xq28 in a female with anorectal malformations. Excluded since the deletion includes 10 additional OMIM genes.

• HI Evidence Comments: Please note: The gene symbol for FAM58A is now CCNQ. Older literature still refers to the previous symbol (FAM58A). STAR syndrome is a rare X-linked dominant disorder characterized by toe Syndactyly, Telecanthus, Anogenital malformations, and Renal malformations. Loss-of-function pathogenic variants in CCNQ has been associated with STAR syndrome. Unger et al. (2008) describe four CCNQ pathogenic loss-of-function variants (3 de novo and 1 maternal inherited) in four unrelated girls with STAR syndrome. Orge et al. (2015) presented a 65 kilobase deletion of chromosome Xq28 encompassing the 5′ end of the CCNQ gene affecting its regulatory region in a mother-daughter pair with X-linked dominant STAR syndrome. The mother had a much more mild presentation of STAR syndrome compared to her daughter. Boczek et al (2017) reported a pathogenic nonsense variant in an 8-year-old female with STAR syndrome and the variants co-segregated with another two affected individuals in this family. Although the proband's mother and maternal half-sister had similar clinical histories, but had variability in phenotypic severity.

NOTE

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity
• TS Evidence Comments: Focal duplication of CCNQ is not identified.

NOTE

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.