RAD21 |
- 3
Haplo
Score - 0
Triplo
Score
Gene Facts External Data Attribution
- HGNC Symbol
- RAD21 (HGNC:9811) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
- HGNC Name
- RAD21 cohesin complex component
- Gene type
- protein-coding gene
- Locus type
- gene with protein product
- Previous symbols
- No previous names found
- Alias symbols
- KIAA0078, hHR21, SCC1
- %HI
- 4.51(Read more about the DECIPHER Haploinsufficiency Index)
- pLI
- 1(Read more about gnomAD pLI score)
- LOEUF
- 0.26(Read more about gnomAD LOEUF score)
- Cytoband
- 8q24.11
- Genomic Coordinates
-
GRCh37/hg19: chr8:117858173-117887015 NCBI Ensembl UCSC GRCh38/hg38: chr8:116845934-116874776 NCBI Ensembl UCSC - MANE Select Transcript
- NM_006265.3 ENST00000297338.7 (Read more about MANE Select)
- Function
- [Double-strand-break repair protein rad21 homolog]: As a member of the cohesin complex, involved in sister chromatid cohesion from the time of DNA replication in S phase to their segregation in mitosis, a function that is essential for proper chromosome segregation, post-replicative DNA repair, and the prevention of inappropriate recombination between repetitive regions (PubMed:11509732). The cohesin complex may also play a role in spindle pole assembly during mitosis (PubMed:11590136). In inter... (Source: Uniprot)
Dosage Sensitivity Summary (Gene)
Dosage ID:
ISCA-20289
Curation Status:
Complete
Issue Type:
Dosage Curation -
Gene
Haploinsufficiency:
Sufficient Evidence for Haploinsufficiency
(3)
Triplosensitivity:
No Evidence for Triplosensitivity
(0)
Last Evaluated:
03/08/2022
Haploinsufficiency (HI) Score Details
HI Score:
3
HI Evidence Strength:
Sufficient Evidence for Haploinsufficiency
(Disclaimer)
HI Disease:
- Cornelia de Lange syndrome Monarch
HI Evidence:
-
PUBMED:
32193685
Krab et al. 2020 gathered a series of 49 individuals from 33 families with what they describe as an "attenuated Cornelia de Lange phenotype" and RAD21 alterations, including 5 de novo LOF variants (p.Gly547Alafs*65, p.Lys406Argfs*4, p.Glu315Glnfs*9, p.Ile206Thrfs*3, and p.Trp23*), 2 LOF variants with unknown inheritance (p.Ser198Argfs*6 and a 27kb deletion of exons 1-9), 2 LOF variants inherited from affected parents (p.Arg586* and c.274 + 1G >A), 1 LOF inherited from unaffected parent (p.Ser235Ilefs*19), and 2 in-frame deletions (p.Gln592del [de novo] and p.Asp541_Gln568del [inherited from an affected mother]).
-
PUBMED:
30716475
Dorval et al. 2019. This is a case report of a 5-year-old male with mild CdLS who carried a de novo frameshift variant in RAD21 (NM_006265: exon 9: c.943_946del; p.Glu315Glnfs*9.
-
PUBMED:
30919572
Al‐Dewik et al. 2019. A frameshift variant (c.1534_1535dupAT; p.Cys513SerfsX4) was identified in a case with suspected Cornelia de Lange syndrome, inheritance is unknown.
-
PUBMED:
33277604
Li et al 2020. This group analyzed the clinical features and the results of genetic testing of 15 patients who were diagnosed with CdLS. One child with mild CdLS carried a frameshift variant in RAD21 (c.1553_1554delAG, p. (Glu518Valfs*18)), with unknown inheritance.
-
PUBMED:
27882533
Kruszka et al. (2019). The paper identified three frameshift RAD21 variants. 1) a heterozygous c.1548delinsTC mutation in the RAD21 gene, predicted to result in a frameshift and premature termination (Glu518ArgfsTer19) in a 7-year-old girl with Cornelia de Lange syndrome-4 with midline brain defects (CDLS4; 614701). It is inherited from her mildly affected father; 2) a heterozygous c.589C-T transition (chr8.117869605G-A, GRCh37) in the RAD21 gene, resulting in a gln197-to-ter (Q197X) was identified in a 14-year-old boy with CDLS4 (unknown inheritance); 3) a heterozygous 8-bp deletion (c.1217_1224del; chr8.117,864,885del8, GRCh37), predicted to result in a frameshift and premature termination (Lys406ArgfsTer4) was identified in a 2-year-old boy with CDLS4 (unknown inheritance)
-
PUBMED:
32696056
Goel and Parasivam (2020) This paper identified a de novo heterozygous nonsense (c.1843G>T; p.Glu615*) substitution in a female fetus with Cornelia de Lange syndrome-4 with midline brain defects (CDLS4; 614701).
HI Evidence Comments:
RAD21 encodes a key component of the cohesion complex, and variants in RAD21 have been associated with Cornelia de Lange Syndrome (CdLS). Limited information on phenotypes attributable to RAD21 variants and genotype-phenotype relationships is currently published. Cornelia de Lange syndrome (CdLS) is characterized by cognitive impairment, growth deficiency, skeletal malformations, distinct facial features such as long eyelashes and thick highly arched eyebrows, and other major system deficiencies like gastrointestinal reflux.
Additional information:
PMID: 30125677
Gudmundsson et al. (2019) reported a "15-month-old boy presenting with developmental delay, distinct Cornelia de Lange syndrome (CdLS)-like facial features, gastrointestinal reflux in early infancy, testis retention, prominent digit pads, and diaphragmatic hernia." Exome sequencing revealed a novel RAD21 variant, c.1774_1776del, p.Gln592del, suggestive of CdLS type 4. Segregation analysis of the two healthy parents confirmed the variant as de novo. The same patient is included in Krab et al. 2020.
PMID:25125236
Ansari et al. also reported a familial case where an unaffected father had passed on a splice donor variant (c.274+1G>A) to his affected daughter with CdLS. The same patient is included in Krab et al. 2020.
PMID: 24378232
In 2014, Minor et al. reported two patients, one with a frameshift variant (c.592_593dupAG, p.Ser198Argfs*6, as unknown inheritance) of assumed de novo origin, and one patient with a maternally inherited inframe deletion, p.Asp541_Gln568del, spanning exon 13. The mother displayed very mild CdLS features. The same patients are included in Krab et al. 2020.
PMID:27882533
In 2017, Boyle et al. report a frameshift variant, c.704delG, p.Ser235Ilefs*19), in four related females in a family. Besides proband, the deletion was found in the mother and the two aunts of the proband, and none of them had been suspected of having CdLS or a cohesinopathy prior to this study (a). The index patient can be classified as mild CdLS, but the other family members do not fulfill the diagnostic criteria of CdLS. The authors state that this study together with previous reports suggests incomplete penetrance associated with RAD21 variants. The same family is included in Krab et al. 2020.
PMID: 27620904
Martínez et al. 2017 identified a de novo c.68G>A, p.(Trp23Ter) variant in a boy with Cornelia de Lange syndrome. The same patient is included in Krab et al. 2020.
Triplosensitivity (TS) Score Details
TS Score:
0
TS Evidence Strength:
No Evidence for Triplosensitivity (Disclaimer)
Genomic View
Select assembly:
(NC_000008.10)
(NC_000008.11)