Successful pregnancies in an adult with Meier‐Gorlin syndrome harboring biallelic CDT1 variants

Abstract

Meier‐Gorlin syndrome is an autosomal recessively inherited disorder of growth retardation, accompanied by microtia and patellae a/hypoplasia and characteristic facies. Pathogenic variants in genes associated with the initiation of DNA replication underlie the condition, with biallelic variants in CDT1 the most common cause. Using 10× Chromium genome sequencing, we report CDT1 variants in an adult female, with an inframe amino acid deletion inherited in trans with a deep intronic variant which likely serves as the branchpoint site in Intron 8. Splicing defects arising from this variant were confirmed through in vitro analysis. At 49 years, she represents the oldest patient with a molecular diagnosis described in the literature and is the first reported patient with Meier‐Gorlin syndrome to have carried a successful pregnancy to term. Both of her pregnancies were complicated by postpartum hemorrhage and upon subsequent necessary hysterectomy, revealed uterine abnormalities. There is scant knowledge on reproductive ability and success in patients with Meier‐Gorlin syndrome. Successful pregnancies among other clinically recognizable forms of primordial dwarfism have also not been described previously. This case is therefore of clinical interest for many forms of inherited growth retardation, and will assist in providing more information and clinical guidance for females of reproductive age.

Genome sequencing for detection of pathogenic deep intronic variation: A clinical case report illustrating opportunities and challenges

“…Expert phenotyping and a priori clinician identification of candidate genes are especially important to narrow the focus of investigation (Lionel et al, 2018). Furthermore, additional genomic data are frequently required to highlight plausible candidates, such as segregation patterns, and in the case of recessive disorders, often a strong candidate coding variant on one allele (Knapp et al, 2021). In silico splicing prediction tools are imperfect, and there is currently no laboratory consensus regarding best practices including combinatorial approaches and significance thresholds.…”

“…There is substantial evidence supporting its benefits for individuals with unexplained phenotypes associated with high genetic heterogeneity (Bick et al, 2019; Clark et al, 2018; Costain et al, 2020; French et al, 2019; Lionel et al, 2018). However, there is also an underappreciated role for GS in individuals suspected to have specific known Mendelian disorders, when the causal DNA variant(s) are not identified by first‐tier tests (Bick et al, 2019; Curtis et al, 2020; Di Scipio et al, 2020; Knapp et al, 2021; Sangermano et al, 2019; Wooderchak‐Donahue et al, 2018).…”

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

“…Variants in CDT1 appear to be the most common cause of MGORS, and much like ORC1 individuals, there is a spectrum of clinical presentation [19,33]. Successful pregnancies have been noted in an adult case with MGORS but the female patient did experience complications requiring a hysterectomy [33].…”

“…Variants in CDT1 appear to be the most common cause of MGORS, and much like ORC1 individuals, there is a spectrum of clinical presentation [19,33]. Successful pregnancies have been noted in an adult case with MGORS but the female patient did experience complications requiring a hysterectomy [33]. While adult cases of MGORS known to the clinical genetics community are rare, several females have noted abnormalities of the reproductive tract including the uterus, suggesting this could be an underreported issue for women with MGORS.…”