Meier-Gorlin Syndrome Panel

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). 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). This complex consists of the origin recognition complex (subunits 1-6), two regulatory proteins (CDC6 and CDT1), and a putative helicase complex (Munnik et al. 2012).

Individuals with ORC1 variants had significantly shorter stature and smaller head circumferences than individuals from other gene categories (Munnik et al. 2012). The majority of MGS variants are missense and splicing variants. Truncating variants are usually associated with a more severe phenotype (Bicknell et al. Nat Genet 43:356-359, 2011). A gross deletion has been reported in the ORC4 gene (Guernsey et al. 2011).

Large series of MGS patients screened for variants in all five MGS genes have not been described in the literature. Bicknell studied 33 individuals with MGS and found ORC1 variants in four of them from three families (Bicknell et al. Nat Genet 43:356-359, 2011). They also found variants in the remaining four genes (ORC4, ORC6, CDT1, and CDC6) in 14 individuals with MGS from nine families.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes 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 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).