TY - JOUR
T1 - Further Delineation of the Microcephaly-Micromelia Syndrome Associated with Loss-of-Function Variants in DONSON
AU - Abdelrahman, Hanadi A.
AU - John, Anne
AU - Ali, Bassam R.
AU - Al-Gazali, Lihadh
N1 - Publisher Copyright:
© 2018 S. Karger AG, Basel. All rights reserved.
PY - 2019/5/1
Y1 - 2019/5/1
N2 - 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.
AB - 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.
KW - Intrauterine growth restriction
KW - Microcephaly-micromelia syndrome
KW - Replication fork stability
UR - http://www.scopus.com/inward/record.url?scp=85062682982&partnerID=8YFLogxK
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U2 - 10.1159/000497337
DO - 10.1159/000497337
M3 - Article
AN - SCOPUS:85062682982
SN - 1661-8769
VL - 10
SP - 171
EP - 176
JO - Molecular Syndromology
JF - Molecular Syndromology
IS - 3
ER -