Format

Send to

Choose Destination
Am J Med Genet A. 2019 Oct;179(10):2056-2066. doi: 10.1002/ajmg.a.61315. Epub 2019 Aug 13.

Biallelic and De Novo Variants in DONSON Reveal a Clinical Spectrum of Cell Cycle-opathies with Microcephaly, Dwarfism and Skeletal Abnormalities.

Author information

1
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
2
Texas Children's Hospital, Baylor College of Medicine, Houston, Texas.
3
Department of Medical Genetics, Kanuni Sultan Suleyman Training and Research Hospital, Istanbul, Turkey.
4
Department of Medical Genetics, Bezmialem University, Istanbul, Turkey.
5
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
6
Bioinformatics Service Facility, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
7
Center for Bioinformatics, University of Hamburg, Hamburg, Germany.
8
Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Virus Genomics, Hamburg, Germany.
9
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.
10
Department of Pediatrics, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas.

Abstract

Co-occurrence of primordial dwarfism and microcephaly together with particular skeletal findings are seen in a wide range of Mendelian syndromes including microcephaly micromelia syndrome (MMS, OMIM 251230), microcephaly, short stature, and limb abnormalities (MISSLA, OMIM 617604), and microcephalic primordial dwarfisms (MPDs). Genes associated with these syndromes encode proteins that have crucial roles in DNA replication or in other critical steps of the cell cycle that link DNA replication to cell division. We identified four unrelated families with five affected individuals having biallelic or de novo variants in DONSON presenting with a core phenotype of severe short stature (z score < -3 SD), additional skeletal abnormalities, and microcephaly. Two apparently unrelated families with identical homozygous c.631C > T p.(Arg211Cys) variant had clinical features typical of Meier-Gorlin syndrome (MGS), while two siblings with compound heterozygous c.346delG p.(Asp116Ile*62) and c.1349A > G p.(Lys450Arg) variants presented with Seckel-like phenotype. We also identified a de novo c.683G > T p.(Trp228Leu) variant in DONSON in a patient with prominent micrognathia, short stature and hypoplastic femur and tibia, clinically diagnosed with Femoral-Facial syndrome (FFS, OMIM 134780). Biallelic variants in DONSON have been recently described in individuals with microcephalic dwarfism. These studies also demonstrated that DONSON has an essential conserved role in the cell cycle. Here we describe novel biallelic and de novo variants that are associated with MGS, Seckel-like phenotype and FFS, the last of which has not been associated with any disease gene to date.

KEYWORDS:

DONSON; Meier-Gorlin syndrome; cell cycle-opathy; femoral-facial syndrome; microcephalic primordial dwarfism; seckel-like syndrome

PMID:
31407851
PMCID:
PMC6936249
[Available on 2020-10-01]
DOI:
10.1002/ajmg.a.61315

Supplemental Content

Full text links

Icon for Wiley
Loading ...
Support Center