LPIN2

Inheritance Pattern: AR

Disease ID:MONDO:0012316

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0012316

Submitter: ClinGen

LPIN2 was first reported in relation to autosomal recessive Majeed syndrome in 2005 (Ferguson PJ et al., PMID: 15994876). The syndrome of pediatric-onset congenital dyserythropoietic anemia and chronic recurrent multifocal osteomyelitis was first described in 1989, along with its association with Sweet’s syndrome (Majeed HA et al., PMID: 2809904). Over the years, case reports have expanded the phenotype to include recurrent fevers, elevated acute phase reactants and hepatosplenomegaly. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, nor phenotypic variability. Therefore, the following disease entities have been lumped into one disease, Majeed syndrome (OMIM:609682). Ten variants (missense, nonsense, and splice site) that have been reported in 7 probands in 5 publications (PMIDs: 33993107, 15994876, 37865862, 27252506, 17330256) are included in this curation. Functional data exists that confirms, p.Ser734Leu, leads to impaired protein function via loss of phosphatidic acid phosphatase activity (PMID:197717560). All probands are homozygous and none are known to be de novo. ClinVar reports at total of 37 P/LP variants which include frameshift, large deletion, and compound heterozygous variants (Bhuyan et al., PMID 33314777) but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss of inhibition. This gene-disease relationship is also supported by in vitro functional assays and cell culture models (PMIDs: 28031477,33314777). Lipin-2 inhibits activation and sensitization of P2X7R, thereby regulating NLRP3 inflammasome assembly. Deficient macrophages have low intracellular cholesterol levels which alter ion currents through the P2X7R. These currents are corrected when cholesterol levels are restored in concordance with decreased inflammasome activation. Patient cells and LPIN2 deficient macrophages demonstrate increased IL-1B expression, caspase 1 activation, and osteoclastogenesis. Pit assays with patient cells demonstrate increased bone resorption. In summary, there is definitive evidence supporting the relationship between LPIN2 and autosomal recessive Majeed Syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Monogenic Autoinflammatory Disease GCEP on the meeting date May 15, 2024. (SOP Version [10])].

Inheritance Pattern: AR

Disease ID:MONDO:0012316

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0012316

Submitter: Orphanet