Skeletal dysplasia

Gene: LRRK1

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

Created: 6 Mar 2022, 6:30 p.m. | Last Modified: 6 Mar 2022, 6:30 p.m.

Panel Version: 2.184

Comment on list classification: Promoting this gene from grey to amber, but with a recommendation for a green rating following GMS review. More than 3 reported cases.

Created: 28 Sep 2021, 9:50 a.m. | Last Modified: 28 Sep 2021, 9:50 a.m.

Panel Version: 2.128

LRRK1 is not associated with any phenotype in OMIM but there is an OMIM entry for Osteosclerotic metaphyseal dysplasia #615198 with no genes associated with it.

OMIM cites the Iida et al. (2016) )(PMID: 27055475) study in which a homozygous intragenic deletion in the LRRK1 gene was found in a boy with OSMD. They found that Lrrk1 KO mice have bone changes were very similar to those seen in in the patient. They also note that no variants in LRRK1 were identified in two other unrelated patients with OSMD.

Created: 28 Sep 2021, 9:49 a.m. | Last Modified: 28 Sep 2021, 9:49 a.m.

Panel Version: 2.127

Green List (high evidence)

A detailed phenotypic picture of Osteosclerotic metaphyseal dysplasia (OSMD) in patients with LRRK1 variants can be seen in table 1 of Howaldt et al (2020).

Lida et al (2016) identified homozygous deletion that is predicted to result in elongation of protein (p.E1980Afs*66) in a child with OSMD. Child was born to consanguineous parents, both heterozygous for variant.

Guo et al (2017) identified a family with OSMD. Healthy, non-consanguineous parents have two children with OSMD that are homozygous for 1bp insertion in LRRK1 that is predicted to result in a frame-shift and produce an elongated protein (p.A1991Gfs*31) without nonsense-mediated mRNA decay. A similar effect seen in Lida et al (2016).

Howaldt et al (2020) shows a patient with a homozygous splice site mutation resulting in near complete skipping of exon 3 in cDNA leading to a frameshift (p.Ala34Profs*33). The variant segregated with disorder in the family with parents being heterozygous for the variant and clinically unaffected.

Miryounesi et al (2020) identified a patient with suspected OSMD from healthy, consanguineous parents. Patient is homozygous for stop gain mutation (c.2785G > T, p.E929X) in LRRK1. Parents are heterozygous for the variant.

Homozygous nonsense variant in LRRK1 also identified in an individual recruited to the 100,000 genomes project for skeletal dysplasia, Osteosclerotic metaphyseal dysplasia is considered a good fit for phenotype.

LRRK1 gene should be included in the skeletal dysplasia panel as a green gene at the next GMS panel update.
Sources: NHS GMS, Literature

Created: 23 Sep 2021, 9:48 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Osteosclerotic metaphyseal dysplasia (OSMD) (OMIM: 615198)

Publications

• 27829680
• 27055475
• 31571209
• 32119750