Novel Compound Heterozygous Variants in the CDC6 Gene in a Russian Patient with Meier-Gorlin Syndrome

Abstract

Background: Meier-Gorlin syndrome (MGS) is a rare genetic syndrome inherited in an autosomal dominant or autosomal recessive manner. The disorder is characterized by bilateral microtia, absence or hypoplasia of the patella, and an intrauterine growth retardation as well as a number of other characteristic features. The cause of the disease is mutations in genes encoding proteins involved in the regulation of the cell cycle (ORC1,

The expanding genetic and clinical landscape associated with Meier-Gorlin syndrome

“…The second case showed a similar genotype, although the missense variant affected a residue in a different domain of MCM7. His set of clinical features was quite different, with normal growth parameters but a progeroid appearance at birth, as well as adrenal insufficiency and lipodystrophysimilar features have been observed in cases with CDC6 or POLD1 variants [13,39]. In both cases, patient-derived cells showed a reduction of MCM7 protein, sufficient to cause a mild reduction in DNA replication in early S phase.…”

“…Such a substitution would likely impact ATPase activity, hampering the ability of CDC6 to disengage from ORC as part of pre-RC assembly [37,38]. The second patient reported was compound heterozygous for a nonsense and a missense variant [39]. In addition to the characteristic features of MGORS, this second individual was severely affected, with features of progeroid appearance at birth and lipodystrophy; features also observed in one individual with MCM7 variants [8], and in other replisome disorders affecting later stages of DNA replication initiation [13].…”

“…The patient had significant short stature and no microcephaly but did present with motor development delays. The residue affected by the substitution, Lys77, lies within a CDK2/ cyclin A phosphorylation motif associated with cytoplasmic translocation to regulate CDC6 activity [39].…”

“…To date, biallelic CDC45 variants have been reported in 19 individuals across 15 families and underlie a broad spectrum of phenotypes that range from a classic MGORS presentation to syndromic craniosynostosis with short stature but no other MGORS features [6,[46][47][48]. The majority of clinically diagnosed MGORS individuals had the clinical triad of short stature, microtia, and patella hypo/aplasia [37][38][39]. MGORS-related genital anomalies (micropenis or clitoromegaly) were reported in at least two individuals and both females of suitable age were affected by mammary hypoplasia [37].…”