Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Meier-Gorlin Syndrome: Clinical Misdiagnosis as Jeune Syndrome, Genetic Testing and Functional Analysis of ORC6 Mutations and the Development of a Prenatal Test

Version 1 : Received: 20 May 2022 / Approved: 23 May 2022 / Online: 23 May 2022 (10:18:24 CEST)

How to cite: Nazarenko, M.S.; Viakhireva, I.V.; Skoblov, M.Y.; Soloveva, E.V.; Sleptcov, A.A.; Nazarenko, L.P. Meier-Gorlin Syndrome: Clinical Misdiagnosis as Jeune Syndrome, Genetic Testing and Functional Analysis of ORC6 Mutations and the Development of a Prenatal Test. Preprints 2022, 2022050292 (doi: 10.20944/preprints202205.0292.v1). Nazarenko, M.S.; Viakhireva, I.V.; Skoblov, M.Y.; Soloveva, E.V.; Sleptcov, A.A.; Nazarenko, L.P. Meier-Gorlin Syndrome: Clinical Misdiagnosis as Jeune Syndrome, Genetic Testing and Functional Analysis of ORC6 Mutations and the Development of a Prenatal Test. Preprints 2022, 2022050292 (doi: 10.20944/preprints202205.0292.v1).

Abstract

Meier–Gorlin syndrome (MGS) is a rare genetic developmental disorder that causes primordial proportional dwarfism, microtia, absent or hypoplastic patellae and other skeletal anomalies. Overlapping skeletal symptoms make MGS difficult to diagnose clinically. We describe a 3-year-old boy with short stature, recurrent respiratory infections, short-rib dysplasia, tower head and facial dysmorphisms who was admitted to the Tomsk Genetic Clinic to verify a clinical diagnosis of Jeune syndrome. Clinical Exome sequencing revealed two variants (compound heterozygosity) in the ORC6 gene: c.2T>C(p.Met1Thr) and c.449+5G>A. In silico analysis showed the pathogenicity of these two mutations and predicted a decrease in donor splicing site strength for c.449+5G>A. An in vitro minigene assay demonstrated that variant c.449+5G>A causes a complete skipping of exon 4 in ORC6 gene. The parents asked for urgent prenatal testing for MGS for the next pregnancy, but it ended in a miscarriage. Thus, this case report may help to prevent MGS misdiagnosis in the future. We also performed in silico and functional analyses of ORC6 mutations and developed a restriction fragment length polymorphism and haplotype-based short-tandem-repeat assay for prenatal genetic testing for MGS. These findings should elucidate MGS aetiology and improve the quality of genetic counselling for affected families.

Keywords

Meier-Gorlin syndrome; Jeune syndrome; ORC6; exon skipping variant; prenatal genetic testing

Subject

LIFE SCIENCES, Genetics

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