Restrictive Dermopathy and Mandibuloacral Dysplasia with Type B Lipodystrophy via the ZMPSTE24 Gene

Restrictive dermopathy (RD; OMIM 275210) is a rare disorder observed in newborns that is characterized by tight, translucent and rigid skin, joint contractures and distinctive craniofacial abnormalities including the hallmark “O” shaped mouth and micrognathia. Newborns with RD rarely live beyond the first week of life. Mandibuloacral dysplasia with type B lipodystrophy (MADB; OMIM 608612) is a progeroid syndrome characterized by mandibular and clavicular hypoplasia, joint contractures, delayed closure of the cranial sutures, atrophic skin, and lipodystrophy. In addition to these typical findings, one case of ZMPTE24-associated MADB was found with a complex presentation including congenital myopathy with fiber type disproportion (Ben Yaou et al. Eur J Hum Genet 19:647-654, 2011). This patient was found to be homozygous for a novel ZMPSTE24 missense variant. A severe presentation of MADB was reported in Japanese siblings who were compound heterozygous for an inactivating nonsense variant and a missense variant (Miyoshi et al. Clin Genet 73: 535–544, 2008).

Restrictive dermopathy and mandibuloacral dysplasia may be caused by variant in the ZMPSTE24 gene or less often by variants in the LMNA gene. ZMPSTE24-associated RD and MADB are inherited in an autosomal recessive manner (Navarro et al. Hum Molec Genet 14:1503-1513, 2005; Agarwal et al. Hum Molec Genet 12:1995-2001, 2003). LMNA-associated RD is inherited in an autosomal dominant manner (Navarro et al. Hum Molec Genet 13:2493-2503, 2004), while LMNA-associated mandibuloacral dysplasia with type A lipodystrophy is inherited in an autosomal recessive manner (Novelli et al. Am J Hum Genet 71:426-431, 2002). ZMPSTE24 is located on chromosome 1p34 and encodes a zinc metalloendoproteinase that is involved in processing farnesylated prelamin A to mature lamin A. Consequently, inactivating variants in the ZMPSTE24 gene lead to loss of expression of lamin A and abnormal patterns of nuclear morphology and mislocalization of lamin-associated proteins (Navarro et al. Hum Molec Genet 13:2493-2503, 2004). The c.1085dupT variant is the most common ZMPSTE24 variant associated with RD and is thought to originate from a European founder (Miner Am J Med Genet 152A:2140–2141). Inactivating variants (nonsense, frame-shift, splice site) are the most common type of variant in the ZMPSTE24 gene.

The prevalence of these disorders is too low to estimate clinical sensitivity. Analytical sensitivity should be high as nearly all ZMPSTE24 variants reported to date are expected to be detected by gene sequencing.

This test provides full coverage of all coding exons of the ZMPSTE24 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).