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A De Novo Mutation in the X-Linked PAK3 Gene Is the Underlying Cause of Intellectual Disability and Macrocephaly in Monozygotic Twins

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A De Novo Mutation in the X-Linked PAK3 Gene Is the Underlying Cause of Intellectual Disability and Macrocephaly in Monozygotic Twins European Journal of Medical Genetics xxx (2017) 1e5 Contents lists available at ScienceDirect European Journal of Medical Genetics journal homepage: http://www.elsevier.com/locate/ejmg A de novo mutation in the X-linked PAK3 gene is the underlying cause of intellectual disability and macrocephaly in monozygotic twins Jozef Hertecant a, b, Makanko Komara c, Aslam Nagi a, Olfat Al-Zaabi d, Waseem Fathallah e, Hong Cui f, Yaping Yang f, Christine M. Eng f, Mohammad Al Sorkhy g, * Mohammad A. Ghattas g, Lihadh Al-Gazali b, Bassam R. Ali c, a Department of Paediatrics, Tawam Hospital, Al-Ain, United Arab Emirates b Department of Paediatrics, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates c Department of Pathology, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates d Fujairah Hospital, Fujairah, United Arab Emirates e Mafraq Hospital, Abu Dhabi, United Arab Emirates f Department of Molecular and Human Genetics, Baylor College of Medicine, Baylor Miraca Genetics Laboratories, Houston, TX 77030, USA g College of Pharmacy, Al Ain University of Science and Technology, Al-Ain, United Arab Emirates article info abstract Article history: Pathogenic variants in theP21 protein (Cdc42/Rac)-activated kinase 3gene (PAK3) lead to a rare non Received 29 May 2016 syndromic X-linked intellectual disability. The protein encoded by this gene forms an activated complex Received in revised form with GTP-bound RAS-like (P21), CDC2 and RAC1 proteins which then mediates a variety of cellular 17 January 2017 processes. So far, mutations in PAK3 gene have been reported in few families affected with intellectual Accepted 18 January 2017 disability associated with neurological manifestations such as speech defect, behavioral problem, brain Available online xxx structural abnormalities, microcephaly and cerebral palsy. In this study whole exome sequencing revealed a de novo likely pathogenic variant in PAK3 gene in monozygotic twins presented with intel- Keywords: de novo mutation lectual disability, speech delay, behavioral problems and macrocephaly. Macrocephaly was noticed in our X-linked patients from birth at 35 weeks of gestation. This aspect of the phenotype has not been previously re- PAK3 ported in other documented cases with pathogenic mutations in PAK3 gene. Our findings extend the Intellectual disability phenotype of this disorder to include macrocephaly and offers further clues to the importance of the Macrocephaly serine/threonine-protein kinase 3 (PAK3) protein in brain development and function. © 2017 Published by Elsevier Masson SAS. 1. Introduction isolated trait or as part of a syndrome and therefore ID is subdivided into syndromic, in which intellectual deficits are associated with Intellectual Disability (ID) is one of the major burdens on health systemic abnormalities and nonsyndromic in which intellectual care systems worldwide. It is defined as a significant limitation both deficits, appear in the absence of other anomalies (Daily et al., in intellectual functioning and in adaptive behavior, covering social 2000; Bradinova et al., 2005; Moeschler and Shevell, 2006). Non- and practical skills that originate before the age of 18 years syndromic ID accounts for 30e50% of all cases and it has been (Schalock et al., 2010). ID is a lifelong disability affecting about estimated that about a quarter of the cases are caused by defects in 2e3% of most populations presenting in infancy or early childhood. single genes (Daily et al., 2000; Bradinova et al., 2005). Variants in Causes of ID are numerous, including environmental and genetic several hundred genes have been identified as causing ID, but many factors but the majority of known causes are of genetic origins cases remain of unknown cause. (Daily et al., 2000; Bradinova et al., 2005). ID might occur as an The prevalence of ID in males is approximately 30% higher than in females (Herbst and Miller, 1980) suggesting a central role of chromosome X located genes in cognitive functions and/or CNS development (Schalock et al., 2010). To date, 122 genes have been * Corresponding author. Department of Pathology, College of Medicine and associated with X-linked intellectual disability (XLID) (Greenwood Health Sciences, United Arab Emirates University, P.O. Box 17666, Al-Ain, United Arab Emirates. Genetic Center, XLID Update March 2015; Stevenson et al., 2012). E-mail address: [email protected] (B.R. Ali). One of the X-linked ID-causing genes is PAK3 which was discovered http://dx.doi.org/10.1016/j.ejmg.2017.01.004 1769-7212/© 2017 Published by Elsevier Masson SAS. Please cite this article in press as: Hertecant, J., et al., A de novo mutation in the X-linked PAK3 gene is the underlying cause of intellectual disability and macrocephaly in monozygotic twins, European Journal of Medical Genetics (2017), http://dx.doi.org/10.1016/j.ejmg.2017.01.004 2 J. Hertecant et al. / European Journal of Medical Genetics xxx (2017) 1e5 by Allen et al., in 1998. Subsequently, several other loss-of-function written consent. Genomic DNA was extracted using Flexigene DNA variants and dominant negative function of PAK3 have been re- kit (QiagenGmbh, Germany) following the manufacturers’ protocol. ported in patients from diverse ethnic backgrounds with non- Whole-exome sequencing for the first twin was performed as a syndromic X-linked intellectual disability (Bienvenu et al., 2000; service at the Baylor Medical Genetics Laboratories, Houston, TX, Gedeon et al., 2003; Peippo et al., 2007; Rejeb et al., 2008) and in USA (www.bcmgeneticlabs.org). Ilimunia platform was used for the some cases with a more complex phenotypes of ID, skin defect and next generation sequencing. The mean coverage of the exome is brain structural abnormalities (Magini et al., 2014). 11e120X whereby 95% of the exome is covered at >20X. Variants PAK3 encodes a member of the P21-activated family of serine/ are filtered using various stringencies of minor allele frequencies, as threonine kinases (PAKs), which are downstream effectors for Rac/ well as mutation databases and disease specific databases and a Cdc42 and Rho GTPases. These proteins are known to regulate team of certified molecular lab directors and medical directors multiple signal transduction pathways, including the MAPK interpret the results based on disease phenotype. The final filtration pathway (Slack-Davis et al., 2003; Beeser et al., 2005) and hence are identified candidate variants in DST, TTN and PAK3 genes. The involved in controlling multiple intracellular processes including genomic DNA surrounding the identified candidate variant was proliferation, cell cycle progression and cytoskeleton remodeling amplified using PCR. Primer sets were designed using Primer3 (Bokoch, 2003). In this article we report a de novo missense mu- software (http://biotools.umassmed.edu/bioapps/primer3_www. tation affecting a monozygotic twin presented with ID, speech cgi) followed by purification of the PCR products using ExoSAP-IT delay behavioral problems and macrocephaly. In addition, we (USB Inc.) Sanger cycle sequencing was performed using 3130xl report variability in the clinical presentation in our patients Genetic Analyzer System (Applied Biosystems). Results were compared to patients reported in the literature with pathogenic analyzed based on NCBI reference sequence number NM_002578. variants in PAK3. 2.2. In silico analysis and protein stability 2. Patients, material and methods Prediction analysis using mutation taster (http://www. mutationtaster.org/), PolyPhen2 (http://genetics.bwh.harvard.edu/ 2.1. Patients, whole-exome sequencing and Sanger sequencing pph2/) and SIFT/Provean (http://sift.jcvi.org/) were used to assess the potential effects of the variants (De Baets et al., 2012; Kumar This study has been approved by Al-Ain District Human et al., 2009). The crystal structure of PAK3 homologous, PAK1, Research Ethics Committees (protocol number 10/09). We ascer- was obtained from the protein data bank (PDB ID: 5DEY). The PAK1 tained a non-consanguineous family with two affected children structure was checked by Molecular Operation Environment (MOE) (Fig. 1A). Peripheral blood samples were collected in EDTA tubes (http://www.chemcomp.com) for any missing atoms using the from the parents and both affected twins after obtaining informed protein preparation module, which was also used to assign pro- tonation states on ionizable groups and to set up partial charges on the protein atoms. The Y429H mutation was generated via the Residue Scan module in MOE. Accordingly, stability results of the wildtype and mutated form of the protein are reported. 3. Results 3.1. Clinical description The two affected children are monozygotic twins (Fig. 1A). The non consanguineous parents have three healthy siblings who are developmentally normal. The affected children were born after a normal pregnancy of 35 weeks gestation. They were noticed to have macrocephaly from birth. At birth, the weight of the first twin was 2.65 kg (P50), length was 47 cm (P50e75) and the head circumference was 34.5 cm (P90). The weight of the second twin was 3.11 kg (P90), length was 57 cm (above P97) and head circumference was 35.3 cm (P97). We evaluated them at the age of nearly 4 years. The first twin did not speak at all in spite of a normal hearing test. Reactive smile was only noticed at the age of 2 years. He sat alone by the age of 9 months and started to walk at the age of 2 years and 9 months but still could not jump, run or walk upstairs without support. He seemed to have autistic features as he did not make eye contact and did not interact with his sibling. However, by history, he does not have other typical features of autism, except that he is unusually scared of loud noises, such as those of vacuum cleaners and blenders. These get him very agitated and make him cry and shout. He is not hyperactive and mainly plays with I-pads and mobile phones.
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