Severe microcephaly

Gene: RAD50

The rating of this gene has been updated following NHS Genomic Medicine Service approval.

Created: 10 Mar 2022, 1:37 p.m. | Last Modified: 10 Mar 2022, 1:37 p.m.

Panel Version: 2.292

Green List (high evidence)

Comment on list classification: There are now a total of 3 unrelated cases (PMIDs: 19409520; 32212377; 33378670) with a RAD50‐related syndrome including microcephaly. This therefore reaches the threshold for promotion of this gene to Green status at the next review (removed 'watchlist' tag and added 'Q2_21_rating' tag)

Created: 1 Apr 2021, 3:48 p.m. | Last Modified: 1 Apr 2021, 3:48 p.m.

Panel Version: 2.106

- PMID: 33378670 (2020) - single patient described with bone marrow failure, immunodeficiency and developmental defects (including microcephaly), who was compound heterozygous for a frameshift and premature stop codon (c.2165dup; p.Glu723Glyfs∗5 - maternally inherited) and in-frame deletion (c.3109_3111del; p.Glu1035del - de novo) in the RAD50 gene.
Functional characterisation using patient-derived fibroblasts indicated defects in DNA replication, DNA repair, and DNA end resection; however, ATM-dependent DNA damage response remained intact. Studies in yeast modelling the variant corresponding to p.Glu1035del produced defects in both DNA repair and Tel1ATM-dependent signalling following thermal activation.

Created: 1 Apr 2021, 3:40 p.m. | Last Modified: 1 Apr 2021, 3:40 p.m.

Panel Version: 2.105

Comment on list classification: Relevant phenotype (two unrelated cases with severe congenital microcephaly) but additional cases required before inclusion of RAD50 on a diagnostic panel.

Rating Amber in anticipation of additional publications/clinical evidence (added to watchlist).

Created: 21 Sep 2020, 3:42 p.m. | Last Modified: 21 Sep 2020, 3:42 p.m.

Panel Version: 2.22

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Nijmegen breakage syndrome-like disorder, OMIM:613078

Publications

• 19409520
• 32212377
• 33378670

Green List (high evidence)

Two individuals reported with bi-allelic variants in this gene showing dysmorphic facial features similar to NBS, short stature, microcephaly, and mild/moderate intellectual disability. Fibroblasts established from one of the individuals showed chromosomal instability and abnormal radioresistant DNA synthesis. The MRE11/RAD50/NBN (MRN) complex is involved in signaling processes inducing the repair of DNA double-strand breaks. Variants in NBN and MRE11 are associated with Nijmegen breakage syndrome (NBS) and ataxia telangiectasia (AT)‐like disorder, respectively, so this gene is a strong biological candidate for this phenotype.
Sources: Literature

Created: 8 Sep 2020, 10:52 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Nijmegen breakage syndrome-like disorder, MIM# 613078

Publications

• 19409520
• 32212377

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