Further Delineation of the Microcephaly-Micromelia Syndrome Associated with Loss-of-Function Variants in DONSON

Abstract

The DONSON gene encodes the downstream neighbor of SON, a replisome component that stabilizes the replication fork during replication. A severe form of microcephalic dwarfism, microcephaly-micromelia syndrome (MIMIS), has been recently associated with DONSON biallelic loss of function. Affected fetuses suffer severe growth restriction, microcephaly, and variable limb malformations which result in intrauterine or perinatal death. All described fetuses carried a homozygous founder mutation (c.1047-9A>G), a splice-altering variant that leads to transcript degradation. We evaluated 2 newborns from a consanguineous Emirati family with severe microcephaly, micromelia, craniofacial dysmorphism, and skeletal abnormalities; both died shortly after birth. Here, we report the second homozygous loss-of-function variant (c.763C>T) in DONSON causing MIMIS, and we provide detailed clinical description of this very rare disorder. In addition, we review all MIMIS cases in the literature and summarize the striking features of this phenotype. This manuscript is aimed to increase the clinical understanding of this rare, extremely severe disorder and encourage clinical and molecular geneticists to consider screening for DONSON loss-of-function variants in families with recurrent pregnancy loss and/or perinatal deaths.

Thanatophoric dysplasia in nonadherent to antenatal care in low middle income country: a rare case reports

“…Consanguinity in the family was mentioned in this case report, raising the likelihood of autosomal recessive inheritance 10 . Recently, biallelic loss of function of DNA replication fork stabilization factor (DONSON) has been linked to a severe form of microcephalic dwarfism called microcephaly-melia syndrome (MIMIS) 11 , 12 . Fetuses with this condition have significant growth restrictions, microcephaly, and a variety of limb deformities, which can cause intrauterine or perinatal mortality.…”

“…Fetuses with this condition have significant growth restrictions, microcephaly, and a variety of limb deformities, which can cause intrauterine or perinatal mortality. Donson offers additional proof that microcephalic dwarfism is frequently caused by genes that encode either part of the DNA replication machinery (replisome) or proteins involved in genome stability 12 .…”

The microcephaly gene Donson is essential for progenitors of cortical glutamatergic and GABAergic neurons

“…Although a wealth of data shows that DONSON mutations lead to PM, skeletal abnormalities, and probably hematopoiesis defects [14,[16][17][18][19][20][21], consequences of DONSON loss of function have not been assessed in animal models. Here, we identify Donson expression in the major proliferation zones of the mouse telencephalon.…”

“…The developmental defects were attributed to decreased checkpoint activity and chromosomal instability due to impaired DONSON function. Subsequent studies linked DONSON mutations to micromelia syndrome, Meier-Gorlin syndrome, Seckel-like syndrome, Femoral Facial syndrome, and microcephaly, short stature and limb abnormalities, which are all characterized by microcephaly as well as skeletal and craniofacial abnormalities [16][17][18][19][20][21]. The wealth of clinical data indicating that DONSON mutations can lead to severe developmental defects are opposed by the lack of studies assessing…”

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

“…Biallelic hypomorphic DONSON variants have previously been found to underlie a clinically distinct primordial dwarfism of severely disproportionate microcephaly and variable skeletal abnormalities mainly present in the upper limb (MISSLA; MIM 617604) [15,51,52]. A third associated phenotype is microcephalic-micromelia syndrome (MIMIS; MIM 251230), a severe form of primordial dwarfism associated with perinatal death [53,54]. Microcephaly in MIMIS patients is severe but proportional to height restriction, with the identified MIMIS variants causing a severe or predicted complete loss of DONSON protein.…”