G C A T T A C G G C A T genes Article Further Delineation of Phenotype and Genotype of Primary Microcephaly Syndrome with Cortical Malformations Associated with Mutations in the WDR62 Gene Ryszard Slezak 1,* , Robert Smigiel 2,* , Ewa Obersztyn 3, Agnieszka Pollak 4, Mateusz Dawidziuk 3 , Wojciech Wiszniewski 3,5, Monika Bekiesinska-Figatowska 6 , Malgorzata Rydzanicz 4,* , Rafal Ploski 4 and Pawel Gawlinski 3,* 1 Department of Genetics, Wroclaw Medical University, 50-368 Wroclaw, Poland 2 Department of Pediatrics and Rare Disorders, Wroclaw Medical University, 50-368 Wroclaw, Poland 3 Department of Medical Genetics, Institute of Mother and Child, 01-211 Warsaw, Poland; [email protected] (E.O.); [email protected] (M.D.); [email protected] (W.W.) 4 Department of Medical Genetics, Medical University of Warsaw, 50-368 Warsaw, Poland; [email protected] (A.P.); [email protected] (R.P.) 5 Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR 97239-3098, USA 6 Department of Diagnostic Imaging, Institute of Mother and Child, 01-211 Warsaw, Poland; [email protected] * Correspondence: [email protected] (R.S.); [email protected] (R.S.); [email protected] (M.R.); [email protected] (P.G.) Citation: Slezak, R.; Smigiel, R.; Obersztyn, E.; Pollak, A.; Dawidziuk, M.; Wiszniewski, W.; Abstract: Type 2 congenital microcephaly (MCPH2) is a brain development disorder characterized by Bekiesinska-Figatowska, M.; primary microcephaly with or without brain malformations. MCPH2 is caused by mutations in the Rydzanicz, M.; Ploski, R.; Gawlinski, WDR62 gene. We present three new patients with MCPH2 and compound heterozygous mutations P. Further Delineation of Phenotype in the WDR62 gene. In all the cases, the parents were healthy and unrelated. All children were and Genotype of Primary clinically diagnosed with congenital microcephaly and retardation of motor and speech development. Microcephaly Syndrome with Sequencing results in the presented patients revealed five new variants in the WDR62 gene (c.4273C>T, Cortical Malformations Associated c.1711_1712insTA, c.1777_1778delGA, c.1642+2T>G, c.194T>A) and one previously described in the with Mutations in the WDR62 Gene. German population (c.2864_2867delACAG). In two of the presented cases, variants in the SMAD4, Genes 2021, 12, 594. https://doi.org/ DKC1, and ATRX genes were also found with unknown effects on the course of the disease. Moreover, 10.3390/genes12040594 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 Academic Editor: Diego Centonze primary microcephaly type 2 caused by mutations in the WDR62 gene. Received: 27 February 2021 Accepted: 17 April 2021 Keywords: WDR62 gene; intellectual disability; microcephaly; MCPH2 Published: 19 April 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in 1. Introduction published maps and institutional affil- Microcephaly Primary Hereditary (MCPH) is a group of brain development disorders, iations. defined as a reduction in the volume of the brain and a secondary reduction in head circumference, usually without changes in brain architecture. The size of the brain is determined by the number of its neurons, and the process of their formation is related to the proper function of the centrosome and especially in mitotic spindle formation, and Copyright: © 2021 by the authors. neuronal migration. A mitotic spindle formation disturbance does not change the functions Licensee MDPI, Basel, Switzerland. of neurons. Until now, many genes involved in these processes have been described, and This article is an open access article several types of MCPH have been distinguished [1]. The basic clinical picture includes distributed under the terms and microcephaly found immediately after birth, at least 2 standard deviations below normal conditions of the Creative Commons age, relatively normal early motor milestones, intellectual disability of variable severity, Attribution (CC BY) license (https:// speech development delay, motor deficit, and inconstant epilepsy. All the described cases creativecommons.org/licenses/by/ were inherited autosomal recessively [2]. 4.0/). Genes 2021, 12, 594. https://doi.org/10.3390/genes12040594 https://www.mdpi.com/journal/genes Genes 2021, 12, 594 2 of 11 Type 2 congenital microcephaly (MCPH2; OMIM 604317) is caused by mutations in the WDR62 gene (WD repeat domain 62) located at locus 19q13.12-q13.2. The gene is 50,230 bps in size and consists of 32 exons and has 9 splice isoforms. It has numerous repeats in wd40 and consists of 10 functional domains. The gene encodes the WDR62 protein of 1523 amino acids. It is a phosphoprotein associated with mitotic spindle poles during prophase to metaphase. This protein is involved in the pathway of the c-Jun N-terminal kinase. Its expression is seen in neural precursor cells and the postmitotic neurons of the developing brain and the ventricular and subventricular zone in the forebrain region. WDR62 plays an important role in the proliferation and migration of neurons and the duplication of centrioles. The lack of this gene’s function leads to a significant decrease in the size of the cerebral cortex [2]. MCPH2 is the second most common type of hereditary microcephaly. So far, 120 cases of the disease have been described in the world. As the disease is inherited autosomal recessively, it has relatively most frequently been described in populations where there is a frequent occurrence of consanguineous marriages. The article describes three new families in which novel mutations of the WDR62 gene were found. 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. Additionally, we have compared the most frequently described clinical symptoms, dysmorphic features, and changes in brain imaging observed in 120 patients described so far from among 64 families with heterozygous and homozygous mutations in the WDR62 gene. 2. Materials and Clinical Results 2.1. Case1 A 4-month-old girl was born in the 38th week of normal pregnancy via cesarean section due to the longitudinal pelvic position. The child’s parents are young, healthy, and unrelated Caucasian people. The girl is their first child. The birth weight was 2680 g and length 52 cm. The Apgar score was 9 in the first minute. Head circumference noted at birth was 29.5 cm (<−2SD). The anterior fontanelle was small and closed quickly. Persistent foramen ovale (PFO) was found in an ECHO examination. Muscle tone was normal. An ultrasound examination of the head revealed a reduced mass of the brain. The milestones of development were achieved by the child with a considerable delay. The hearing and vision tests, as well as the metabolic tests (GC-MS, MS/MS, amino acids profile), were normal. TORCH infections were also excluded. At 4 months of age, she weighed 5.2 kg and was 59 cm long. Physical examination showed microcephaly, prominent occiput, and upslanted palpebral fissures (Figure1a). MRI of the head showed that the frontal and parietal lobes, as well as the temporal and occipital lobes in the right hemisphere of the brain exhibit polymicrogyria and closed schizencephaly is visible in this hemisphere. There is a significant asymmetry of the hemispheres in the brain with the right one much smaller than the left one and additionally hypoplasia of the corpus callosum, and a falx cerebri defect (Figure1d–g). The EEG record showed low-voltage 5 Hz waves. GenesGenes 20212021, ,1212, ,x 594 FOR PEER REVIEW 33 of of 11 11 FigureFigure 1. 1. DysmorphicDysmorphic facial facial features of individuals withwithWDR62 WDR62mutations: mutations: case case 1, 1, three three year year old old girl girl (a ),(a case), case 2, two2, two year year old oldboy boy (b) and(b) and case case 3, one 3, yearone andyear seven and seven days olddays boy old (c ).boy MRI (c analysis). MRI analysis of case 1of with case microcephaly 1 with microcephaly when she when was 19days she was old 19dayrevealeds old a disproportionatelyrevealed a disproportionately small brain small compared brain to compared the cerebellum to the (cerebellumd,e) and disproportion (d,e) and disproportion of the cerebral of hemispheres:the cerebral hemispheres:R << L (e,g). FullyR << L formed, (e,g). Fully thin formed, corpus callosum thin corpus (d). callosum Polymicrogyria (d). Polymicrogyria and closed-lip and schizencephaly closed-lip schizencephaly in the right cerebral in the righthemisphere cerebral andhemisphere simplified and gyral simplifie patternd gyral in the pattern left one in the (f, gleft). Caseone (f 3,,g a). 7-month-oldCase 3, a 7-month boy- withold boy microcephaly—revealed with microcephaly— revealeddisproportionately disproportionately small brain small compared brain compared to the cerebellum to the (cerebellumh,i), dysgenesis (h,i), of dysgenesis the corpus of callosum the corpus (h) and callosum simplified (h) gyraland simplified gyral pattern (i,j). Reduced white matter volume with posterior horn−dominant enlargement of the lateral pattern (i,j). Reduced white matter volume with posterior horn−dominant enlargement of the lateral ventricles (j). ventricles (j). 2.2.2.2. Case Case 22 AA 20 20-month-old-month-old boyboy was was born born at termat term in the in 40th theweek 40th ofweek the mother’s of the mother’ first pregnancy.s first pregnancy.His birth weight His birth was 3230weight g, and was his 323 Apgar0 g, score and washis 10.Apgar The headscore circumference was 10. The noted head at circumferencebirth was 31 cm noted (−2 at SD). birth During was 31 pregnancy, cm (−2 SD the). During mother pregnancy, felt fetal movements the mother well. felt Afterfetal movementsbirth, the newborn well. After had birth, no defects the newborn of the internal had no organs, defects apartof the from internal microcephaly.