ZMPSTE24

Inheritance Pattern: AR

Disease ID:MONDO:0800042

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0012074

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0800042

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0800042

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0010143

Submitter: ClinGen

​​The ZMPSTE24 gene is located on chromosome 1 at 1p34.2 and encodes the zinc metallopeptidase STE24 protein, an integral membrane protein crucial for the final step in the biogenesis of lamin A (encoded by LMNA), a structural protein component of the nuclear lamina involved in nuclear shape, nuclear pore complex spacing, and resistance to mechanical stress. ZMPSTE24 was first reported in relation to autosomal recessive lethal restrictive dermopathy in 2005 (Navarro et al., 2005 PMID:15843403). Lethal restrictive dermopathy is a congenital onset disorder that is lethal in the perinatal period (stillbirth or newborn death within the first week of life). It is characterized by rigid, translucent and tightly adherent skin with erosions and scaling, facial dysmorphism (small mouth, small pinched nose, and micrognathia), arthrogryposis multiplex/fetal akinesia or hypokinesia deformation sequence (FADS), thin dysplastic bipartite clavicles, overtubulated long bones, and pulmonary hypoplasia. Variants in ZMPSTE24 have also been reported in association with the related non-lethal progeroid disorders, mandibuloacral dysplasia with type B lipodystrophy (MADB) and Hutchinson-Gilford progeria syndrome (HGPS). In vitro studies with recombinant mutated ZMPSTE24 demonstrate that the severity of the pathology caused by ZMPSTE24 variants correlates with the residual enzymatic activity of the mutated enzyme (Barrowman et al., 2012 PMID:22718200). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found there was sufficient phenotypic variability and differences in the molecular mechanisms to support splitting these disorders into two distinct disease entities: lethal restrictive dermopathy (OMIM: 275210), and mandibuloacral dysplasia with type B lipodystrophy (OMIM: 608612) lumped with Hutchinson-Gilford progeria syndrome. Autosomal recessive mandibuloacral dysplasia with type B lipodystrophy has been curated separately. Six variants (frameshift, nonsense, and splice) that have been reported in 5 probands across 5 publications (Morais et al., 2009 PMID:19020898, Lu et al., 2013 PMID:23597553, Jagadeesh et al., 2009 PMID:19383993, Sander et al., 2008 PMID:18671782, Smigiel et al., 2010 PMID:20101687) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is known to be complete loss of function. This gene-disease relationship is also supported by animal models and in vitro functional assays (Pendas et al., 2002 PMID:11923874, Sander et al., 2008 PMID:18671782, Moulson et al., 2005 PMID:16297189). In particular, in vitro assays using patient cells demonstrate an accumulation of prelamin A that is absent in healthy control cells (PMIDs:18671782, 16297189). Knockout mice display abnormalities overlapping with those of mice lacking A/C-type lamin and with human phenotypes related to lamin A deficiencies (PMID:11923874). In summary, ZMPSTE24 is definitively associated with autosomal recessive lethal restrictive dermopathy. 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 Syndromic Disorders Gene Curation Expert Panel on the meeting date 06.02.2021 (SOP Version 8). Data provided by the ClinGen Prenatal GCEP from September 17, 2025 secondary analysis Prenatal features of lethal restrictive dermopathy include reduced fetal movements, tachycardia, distress, fetal growth restriction, and premature preterm rupture of membranes (PPROM). Probands are consistently preterm (often born between 30-33 weeks gestation) and low birth weight (PMIDs: 19020898, 23597553, 18671782, 20101687, 34647350). There are reports of stillbirth (PMID 23597553). Two of the 14 cases with prenatal features have included placenta previa (PMID:18671782). One case with prenatal features of minor oligohydramnios (amniotic fluid index = 8) and spontaneous complete chorioamniotic membrane separation (CCMS) has been reported (PMID:19504603). All reported cases have been neonatal lethal.

Inheritance Pattern: AR

Disease ID:MONDO:0012074

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0010143

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0012074

Submitter: ClinGen

The ZMPSTE24 gene is located on chromosome 1 at 1p34.2 and encodes the zinc metallopeptidase STE24 protein, an integral membrane protein crucial for the final step in the biogenesis of lamin A (encoded by LMNA), a structural protein component of the nuclear lamina involved in nuclear shape, nuclear pore complex spacing and resistance to mechanical stress. ZMPSTE24 was first reported in relation to autosomal recessive mandibuloacral dysplasia with type B lipodystrophy (MADB) in 2003 (Agarwal et al., 2003 PMID:12913070). MADB is an infancy/early childhood onset disorder (by age 2 years), with patients surviving into the third decade of life or later. It is characterized by mandibular hypoplasia, dental abnormalities, bird-like facies, joint contractures, a/hypoplastic clavicles, acral osteolysis, skin hyperpigmentation, absent or sparse hair (total or subtotal alopecia), skin atrophy, generalized lipodystrophy, and short stature. Variants in ZMPSTE24 have also been reported in association with the related, non-lethal progeroid disorder, Hutchinson-Gilford progeria syndrome (HGPS), and the lethal progeroid disorder, lethal restrictive dermopathy. In vitro studies with recombinant mutated ZMPSTE24 demonstrate that the severity of the pathology caused by ZMPSTE24 variants correlates with the residual enzymatic activity of the mutated enzyme (Barrowman et al., 2012 PMID:22718200). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no phenotypic variability or differences in the molecular mechanisms between MADB and HGPS. Therefore, the following disease entities have been lumped into one disease entity, mandibuloacral dysplasia with type B lipodystrophy (OMIM:608612) and Hutchinson-Gilford progeria syndrome. We found there was sufficient phenotypic variability and differences in the molecular mechanisms between MADB and lethal restrictive dermopathy to support splitting these disorders into two distinct disease entities. Autosomal recessive lethal restrictive dermopathy (OMIM:275210) has been curated separately. Thirteen variants (frameshift, nonsense, and missense) that have been reported in 8 probands across 8 publications (PMID:12913070, Agarwal et al., 2006 PMID:17152860, Cunningham et al., 2010 PMID:20550970, Miyoshi et al., 2008 PMID:18435794, Ahmad et al., 2010 PMID:20814950, Ben Yaou et al., 2011 PMID:21267004, Harhouri et al., 2016 PMID:27409638, Hitzert et al., 2020 PMID:31856865) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is known to be partial loss of function. This gene-disease relationship is also supported by animal models and in vitro functional assays (Pendas et al., 2002 PMID:11923874, PMID:21267004, PMID:18435794). In particular, in vitro assays using patient cells demonstrate an accumulation of prelamin A in addition to the lamins A and C also observed in WT cells. No accumulation of prelamin A was observed in heterozygous carriers or healthy control cells (PMID:21267004, PMID:18435794). Knockout mice show severe growth retardation, loss of subcutaneous fat layer, skeletal abnormalities including small mandible and bone fragility, loss of fur, and premature death (average lifespan of 20 weeks), likely due to dilated cardiomyopathy and heart failure. Mice also show muscular dystrophy in addition to the cardiac pathology (PMID:11923874). Of note, the similarity between the knockout mouse phenotype and the human MADB phenotype supported identification of ZMPSTE24 as candidate gene for the disorder. In summary, ZMPSTE24 is definitively associated with autosomal recessive mandibuloacral dysplasia with type B lipodystrophy. 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 Syndromic Disorders Gene Curation Expert Panel on the meeting date 06.02.2021 (SOP Version 8). Monogenic Diabetes Gene Curation Expert Panel (MDEP) amendment: In addition to the classical features of mandibuloacral dysplasia with type B lipodystrophy (MADB), affected individuals may develop metabolic complications of lipodystrophy, most commonly progressive insulin resistance and diabetes mellitus, with reported ages of onset ranging from approximately 13 years into the third decade of life (PMIDs: 17152860, 21267004, 20550970). Other described metabolic features include hypertriglyceridemia and steatotic liver disease (PMIDs: 20550970, 21267004). These abnormalities are presumed to arise from generalized loss of adipose tissue, which limits physiologic lipid storage and contributes to impaired insulin signaling and dysregulated glucose homeostasis. A small number of individuals with ZMPSTE24 variants and MADB have also been reported to develop rapidly progressive chronic kidney disease and/or focal segmental glomerulosclerosis, although the association between ZMPSTE24-related MADB and this renal phenotype is not yet well established (PMIDs: 17152860, 21267004). Because many published reports focus on children in their first decade of life, there is limited information regarding the long-term clinical course and the age-related penetrance of metabolic complications, underscoring the importance of ongoing follow-up into adulthood.

Inheritance Pattern: AD

Disease ID:MONDO:0010143

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0012074

Submitter: Genomics England PanelApp

Inheritance Pattern: AR

Disease ID:MONDO:0012074

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0008310

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0012074

Submitter: Labcorp Genetics (formerly Invitae)