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.