A novel homozygous LRRK1 stop gain mutation in a patient suspected with osteosclerotic metaphyseal dysplasia

Ann Hum Genet. 2020 Jan;84(1):102-106. doi: 10.1111/ahg.12352. Epub 2019 Sep 30.


Osteosclerotic metaphyseal dysplasia (OSMD) is a very rare autosomal-recessive disorder and a distinctive type of osteopetrosis, characterized mainly by skeletal fractures and deformity, osteosclerosis, and sometimes hypotonia, developmental delay, and seizures. Sequence variants in the leucine-rich repeat kinase 1 (LRRK1) gene underlying OSMD have been reported previously. In the present study, we investigated a 14-year-old girl suspected with OSMD in a consanguineous family of Iranian origin segregating the disease in an autosomal-recessive manner. The patient had severe short stature, multiple sclerotic lesions, sandwich vertebrae, Erlenmeyer flask deformity, and looser zones. The multifocal active bony pathology suggested multifocal bony inflammation or multiple looser fractures. Whole-exome sequencing followed by Sanger sequencing confirmation revealed a novel homozygous stop gain mutation (c.G2785T, p.E929X) in the LRRK1 gene. This is the first mutation in the LRRK1 gene, underlying OSMD, in the Iranian population and the third case worldwide. The mutation is located in the C terminal of the Roc domain, distinct from domains affected in the previous two LRRK1 mutations. Additionally, a new group of clinical indications different from the two previous cases is discussed.

Keywords: LRRK1; skeletal dysplasia; whole-exome sequencing.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Amino Acid Sequence
  • Codon, Nonsense
  • Female
  • Gain of Function Mutation*
  • Humans
  • Osteochondrodysplasias / genetics*
  • Osteochondrodysplasias / pathology
  • Osteosclerosis / genetics*
  • Osteosclerosis / pathology
  • Prognosis
  • Protein Serine-Threonine Kinases / genetics*
  • Sequence Homology


  • Codon, Nonsense
  • LRRK1 protein, human
  • Protein Serine-Threonine Kinases

Supplementary concepts

  • Pyle disease