Integrated genome and transcriptome sequencing identifies a noncoding mutation in the genome replication factor DONSON as the cause of microcephaly-micromelia syndrome

By G. Evrony, D. Cordero, Jun Shen, Jennifer N. Partlow, T. Yu, Rachel E. Rodin, R. Hill, Michael E. Coulter, A. Lam, D. Jayaraman and 24 more. 2017

39 citations recorded by the source corpus.

While next-generation sequencing has accelerated the discovery of human disease genes, progress has been largely limited to the “low hanging fruit” of mutations with obvious exonic coding or canonical splice site impact. In contrast, the lack of high-throughput, unbiased approaches for functional assessment of most noncoding variants has bottlenecked gene discovery. We report the integration of transcriptome sequencing (RNA-seq), which surveys all mRNAs to reveal functional impacts of variants at the transcription level, into the gene discovery framework for a unique human disease, microcephaly-micromelia syndrome (MMS). MMS is an autosomal recessive condition described thus far in only a single First Nations population and causes intrauterine growth restriction, severe microcephaly, craniofacial anomalies, skeletal dysplasia, and neonatal lethality. Linkage analysis of affected families, including a very large pedigree, identified a single locus on Chromosome 21 linked to the disease (LOD > 9). Comprehensive genome sequencing did not reveal any pathogenic coding or canonical splicing mutations within the linkage region but identified several nonconserved noncoding variants. RNA-seq analysis detected aberrant splicing in DONSON due to one of these noncoding variants, showing a causative role for DONSON disruption in MMS. We show that DONSON is expressed in progenitor cells of embryonic human brain and other proliferating tissues, is co-expressed with components of the DNA replication machinery, and that Donson is essential for early embryonic development in mice as well, suggesting an essential conserved role for DONSON in the cell cycle. Our results demonstrate the utility of integrating transcriptomics into the study of human genetic disease when DNA sequencing alone is not sufficient to reveal the underlying pathogenic mutation.

Subfields: Cancer Research, Molecular Biology, Plant Science

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Citations in the corpus

In silico protein interaction screening uncovers DONSON’s role in replication initiation (2023, background): “DONSON is essential for cell proliferation inmammals (24).”
Biallelic and De Novo Variants in DONSON Reveal a Clinical Spectrum of Cell Cycle-opathies with Microcephaly, Dwarfism and Skeletal Abnormalities (2019, background): “Most recently, biallelic mutations in DONSON have been identified in families with MPD phenotypes of varied severity and clinical description, including Microcephaly micromelia syndrome (MMS, OMIM 251230), Microcephaly, short stature, and limb abnormalities (MISSLA, OMIM 617604), and microcephalic p”
The expanding genetic and clinical landscape associated with Meier-Gorlin syndrome (2023, background): “Given the early embryonic lethality of a mouse knockout model [54], a rescue via an alternative transcript could be possible to explain the extended survival in MIMIS individuals.”
DNSN-1 recruits GINS for CMG helicase assembly during DNA replication initiation in C. elegans (2023, unknown): “These findings provide a model for understanding the human ortholog ofDNSN-1, knownasDONSON (downstream neighbor of SON), which was previously identified as a genome stability factor that is mutated in microcephalic primordial dwarfism (33, 34).”