Further Delineation of Phenotype and Genotype of Primary Microcephaly Syndrome with Cortical Malformations Associated with Mutations in the WDR62 Gene

Abstract

Type 2 congenital microcephaly (MCPH2) is a brain development disorder characterized by primary microcephaly with or without brain malformations. MCPH2 is caused by mutations in the WDR62 gene. We present three new patients with MCPH2 and compound heterozygous mutations in the WDR62 gene. In all the cases, the parents were healthy and unrelated. All children were clinically diagnosed with congenital microcephaly and retardation of motor and speech development. Sequencing results in the presented patients revealed five new variants in the WDR62 gene (c.4273C>T, c.1711_1712insTA, c.1777_1778delGA, c.1642+2T>G, c.194T>A) and one previously described in the German population (c.2864_2867delACAG). In two of the presented cases, variants in the SMAD4, DKC1, and ATRX genes were also found with unknown effects on the course of the disease. Moreover, in the article we collected and compared the most common clinical symptoms, dysmorphic features, and changes in radiographic examinations of the brain observed in 120 patients with recessive primary microcephaly type 2 caused by mutations in the WDR62 gene.

Autosomal Recessive Primary Microcephaly: Not Just a Small Brain

“…MCPH is a group of rare heterogeneous neurodevelopmental disorders characterized by intellectual disability and a significant reduction in the brain volume reflected by a reduction in the head circumference already at birth ( Kaindl et al, 2010 ; Zaqout et al, 2017 ; Slezak et al, 2021 ). The reduction in brain volume in MCPH cases affects disproportionately the neocortex, though without obvious changes in the cortical organization ( Kaindl et al, 2010 ; Kraemer et al, 2011 ; Jayaraman et al, 2018 ).…”

Autosomal Recessive Primary Microcephaly (MCPH) and Novel Pathogenic Variants in <b><i>ASPM</i></b> and <b><i>WDR62</i></b> Genes

“…On the other hand, we evaluated previous studies investigating the geographical distribution of cases with ASPM and WDR62 variants. For variants of the WDR62 gene, the Turkish population constitutes the most common number of families per country after the Pakistani community [Slezak et al, 2021], while the Turkish population exhibits a lower number of families per country for variants of the ASPM gene [Létard et al, 2018]. As a result of these findings, we suggest that the WDR62 gene might be more prominent in the Turkish population.…”

“…In the previous literature, few cases carrying compound heterozygous variants for the WDR62 gene have been reported. Some of these studies determined polymicrogyria related to compound heterozygous variants of the WDR62 gene [Murdock et al, 2011;Slezak et al, 2021].…”

Autosomal recessive primary microcephaly type 2 associated with a novel WDR62 splicing variant that disrupts the expression of the functional transcript

“…WDR62 is primarily expressed in the forebrain, especially in the ventricular and subventricular zones (25). The asymmetrical development of the patient's brain cortex and ventricles, as observed in MRI findings from our and other studies, remains unexplained (11,17,18). In our patient, the more severely dysplastic right cerebral hemisphere corresponded with a shorter left limb, suggesting that cerebral asymmetry and cortical malformations might lead to physical disabilities, such as limb length discrepancies and gait abnormalities, even though MCPH is not typically linked with malformations outside the central nervous system.…”

“…MCPH2, the second most frequent type of MCPH, is characterized by severe motor handicap, epilepsy, and intellectual disability and is associated with a poor prognosis (10)(11)(12). Brain magnetic resonance imaging (MRI) in MCPH2 patients typically reveals a reduction in brain volume and cortical malformations, including neuronal heterotopia, pachygyria, schizencephaly, and microlissencephaly (11,(13)(14)(15)(16)(17)(18).…”