Meier-Gorlin Syndrome via the CDT1 Gene

Meier-Gorlin syndrome (MGS) is a form of primordial dwarfism, characterized by severe intrauterine and postnatal growth retardation, microcephaly, bilateral microtia, and aplasia or hypoplasia of the patellae (Bongers et al. Am J Med Genet 102:115-124, 2001). Pulmonary emphysema, feeding problems, various skeletal abnormalities, genitourinary anomalies, and mammary hypoplasia frequently accompany this disorder. Infants typically have a small mouth with full lips and micrognathia, whereas in adults, a high forehead and a more prominent, narrow nose with a broad nasal bridge are distinguishable (Munnik et al. Eur J Hum Genet 20: 598-606, 2012). The characteristic facial features may gradually change with age.

MGS is a rare autosomal recessive disorder. Recently, variants in five genes from the pre-replication complex (ORC1, ORC4, ORC6, CDT1, and CDC6) were identified in individuals with MGS (Bicknell et al. Nat Genet 43:350-355, 2011; Bicknell et al. Nat Genet 43:356-359, 2011; Guernsey et al. Nat Genet 43:360-364, 2011). Testing for all five genes is available. The pre-replication complex forms at origins of DNA replication and is essential to initiate genome replication (Nishitani et al. Nature 404:625-628, 2000; Bell et al. Nature 357:128-134, 1992). CDT1 encodes the chromatin licensing and DNA replication factor 1, a regulatory protein required for DNA replication at multiple stages of development (Whittaker et al. Genes Dev 14:1765-1776, 2000). Reported variants in CDT1 include missense and nonsense variants (Bicknell et al. Nat Genet 43:356-359, 2011; Guernsey et al. 2011).

MGS is a rare condition. Series of MGS patients screened for CDT1 variants have not been described in the literature. This test has been designed to detect >99% of point variants published to date.

This test provides full coverage of all coding exons of the CDT1 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).