Skeletal dysplasia

Gene: RAD21

Comment on list classification: Although limb abnormalities are a common feature of CdLS, only minor skeletal anomalies are associated with RAD21 variants. Other prominent features such as ID are more likely to prompt testing and therefore maintaining the Amber rating on skeletal panels for now.

Created: 15 Nov 2022, 12:07 p.m. | Last Modified: 15 Nov 2022, 12:07 p.m.

Panel Version: 2.226

Krab et al. 2020 (PMID: 32193685) collated details on 33 unrelated families (previously and newly published) with RAD21 alterations. In the 22 families with sufficient clinical data available, authors noted that major limb malformations are generally not present. However, minor skeletal anomalies such as clinodactyly of fifth finger (13), camptodactyly (3), scoliosis (2), hip dislocation/dysplasia (2) are reported.

Created: 15 Nov 2022, 12:02 p.m. | Last Modified: 15 Nov 2022, 12:02 p.m.

Panel Version: 2.225

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Cornelia de Lange syndrome 4, OMIM:614701

Publications

• 32193685

Green List (high evidence)

Limb hypoplasia-reduction defects gp of SD- >3 cases; Review on behalf of Tracy Lester

Created: 6 Mar 2019, 11:44 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Cornelia de Lange syndrome 4 614701

I don't know

Comment on list classification: Promoted from red to amber. 2 cases reported in OMIM with SNV and short stature (1 case) and limb defects.

Created: 20 Nov 2019, 2:23 p.m. | Last Modified: 21 Nov 2019, 11:57 p.m.

Panel Version: 1.244

Associated with Cornelia de Lange syndrome 4 614701 in OMIM. Clinical features listed include short stature and limb defects.

OMIM: - 2 cases reported in OMIM with Cornelia de Lange syndrome-4 (PMID: 22633399, Deardorff et al 2012) with de novo heterozygous missense mutations in RAD21. Phenotypic features include Clinodactyly, short fingers (1 patient) and thin fingers (1 patient) and additional skeletal features of pectus carinatum, coxa vara, short femoral neck in one case. An additional 3 patients with overlapping deletions covering RAD21, aswell as other genes, were reported.

Other publications with patients with Cornelia de Lange and RAD21 variants but no major skeletal phenotype:

PMID: 30716475 - Dorval et al 2019 - 1 patient - mild phenotype - gastro-oesophageal reflux, progressive microcephaly, which stabilised at about – 3SD, moderate fine motor delay and speech delay.

PMID: 24378232 - Minor et al., 2014 - 2 patients with atypic Cornelia de Lange. Patient 1 - in frame deletion of exon 13 - presented with developmental delay, hypospadias, inguinal hernia and dysmorphic features, mild 5th finger clinodactyly. This deletion was found to be inherited from the mother who had a history of melanoma and other unspecified medical problems.
Patient 2 - c.592_593dup frameshift mutation - presented with developmental delay, characteristic facial features, hirsutism, and hand and feet anomalies (clinodactyly, syndactyly). The mother had the same frameshift mutation showing incomplete penetrance.

PMID: 27882533 - Boyle et al., 2017 - patient with microcephaly and classical CdLS facial features with a single bp deletion (c.704delG) in RAD21 predicted to result in a premature stop codon [p.(Ser235Ilefs*19)]. The deletion was found in the mother and the two aunts of the index patient, and none of them had been suspected of having CdLS or a cohesinopathy prior to this study - suggests incomplete penetrance.

PMID: 27620904 - Martinez et al., 2017 - 92 patients recruited with syndromic intellectual disability. 1 patient identified with a variant in RAD21. A diagnosis of CdLS was made.

Created: 7 May 2019, 7:29 p.m. | Last Modified: 21 Nov 2019, 11:55 p.m.

Panel Version: 1.244

This gene was part of an initial gene list collated by Tracy Lester, Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, February 2019 on behalf of the GMS Musculoskeletal Specialist Group; Gene symbol submitted: RAD21; Initial rating suggestion: green

Created: 6 Mar 2019, 11:36 a.m.

Comment when marking as ready: Associated with phenotype in OMIM and G2P. At least two variants reported

Created: 29 Jul 2016, 1:49 p.m.

Green List (high evidence)

Tier 3

Created: 17 Jun 2016, 8:07 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Cornelia de Lange syndrome 4 614701

Variants in this GENE are reported as part of current diagnostic practice