1 | Introduction
Microcephaly is a prevalent phenotype of patients with
neurodevelopmental problems (Abuelo, 2007; Vargas, Allred, Leviton, &
Holmes, 2001). It is defined as an occipitofrontal circumference (OFC)
lower than the third percentile or more than two standard deviations
below the mean for sex, age, and ethnicity. Patients with microcephaly
show various neurologic manifestations, including psychomotor problems,
delayed developments, and epilepsy, which are frequently accompany by
facial dysmorphism, skeletal anomalies, and congenital structural
anomalies in the major organs (Vargas, Allred, Leviton, & Holmes,
2001). Recognition of microcephaly can prompt clinicians to investigate
its causes.
The fundamental size of the brain is determined by neuronal progenitor
cells formed at conception and that undergo cell divisions. During this
process, microcephaly may be caused by deficiency of neuropils,
increased apoptosis of progenitor cells, or improper mitosis of these
cells, which is defined as primary microcephaly (Gilmore, & Walsh,
2013). Most primary microcephaly occurs due to the failure of
neurogenesis or destructive prenatal events associated with
environmental or maternal conditions. On the other hand, children with
secondary microcephaly are born with normal head circumference (HC)s and
then show a progressive decrease HC with age. Secondary microcephaly
represents abnormal neuronal development after birth or a perinatal
brain insults (Woods, & Parker, 2013). Children with microcephaly have
OFCs at the outer limits of the normal distribution and low for their
age group. Both categories of microcephaly have various causes,
including congenital infection, perinatal problems such as hypoxia or a
maternal medical condition, or genetic causes (Abuelo, 2007), and the
distinction between them helps clinicians isolate the preferential
etiologies. In addition, accompanying anomalies or facial dysmorphism
can provide clues to determine the exact cause of microcephaly (von der
Hagen et al., 2014).
In previous studies, genetic causes of microcephaly showed an autosomal
recessive inheritance pattern (Darvish et al., 2010; Sajid Hussain et
al., 2013). With the development of next-generation sequencing, genetic
causes of neurodevelopmental disorders, including microcephaly, have
been identified (Hamdan et al., 2014; Najmabadi et al., 2011; Thevenon
et al., 2016). To date, only three studies have used whole exome
sequencing (WES) to investigate genetic causes of microcephaly in
microcephaly cohorts (Boonsawat et al., 2019; Rump et al., 2016; Shaheen
et al., 2019). One study determined disease-causing genes in 11 out of
38 patients who had highly heterogeneous clinical and radiologic
phenotypes. It revealed that autosomal recessive disorders are highly
prevalent among the patients with microcephaly (Rump et al., 2016).
Shaheen et al. (2019) identified potentially causal genetic variants in
104 out of 137 families. They found variants in novel and previously
reported genes that were the causes of microcephaly with established
disease phenotypes. In addition, the authors showed overlap in the
genetic causes of microcephaly with genes underlying microcephalic
primordial dwarfism. A recent comprehensive genetic analysis based on
chromosomal microarray (CMA) and WES detected causative variants in
48.4% of patients (30/62) and analyzed the differences in clinical
severity and genetic variants between primary and secondary microcephaly
(Boonsawat et al., 2019). Each of these studies covered different
characteristics of race, consanguinity, and brain imaging findings.
However, there has been no study of an Asian population based
exclusively on a microcephaly cohort.
We aimed to comprehensively analyze the genomic and phenotypic features
of Korean patients with microcephaly. We tried to delineate clinical
features associated with causative genes to contribute to genetic
investigations of patients with microcephaly.