title: A de novo mutation in the X-linked PAK3 gene is the underlying cause of intellectual disability and macrocephaly in monozygotic twins.
abstract: Pathogenic variants in theP21 protein (Cdc42/Rac)-activated kinase 3gene (PAK3) lead to a rare non syndromic X-linked intellectual disability. The protein encoded by this gene forms an activated complex with GTP-bound RAS-like (P21), CDC2 and RAC1 proteins which then mediates a variety of cellular processes. So far, mutations in PAK3 gene have been reported in few families affected with intellectual disability associated with neurological manifestations such as speech defect, behavioral problem, brain 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 intellectual disability, speech delay, behavioral problems and macrocephaly. Macrocephaly was noticed in our patients from birth at 35 weeks of gestation. This aspect of the phenotype has not been previously reported in other documented cases with pathogenic mutations in PAK3 gene. Our findings extend the phenotype of this disorder to include macrocephaly and offers further clues to the importance of the serine/threonine-protein kinase 3 (PAK3) protein in brain development and function.
authors.affiliation: Department of Paediatrics, Tawam Hospital, Al-Ain, United Arab Emirates; Department of Paediatrics, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates.
authors.forename: Jozef
authors.initials: J
authors.lastname: Hertecant
authors.affiliation: Department of Pathology, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates.
authors.forename: Makanko
authors.initials: M
authors.lastname: Komara
authors.affiliation: Department of Paediatrics, Tawam Hospital, Al-Ain, United Arab Emirates.
authors.forename: Aslam
authors.initials: A
authors.lastname: Nagi
authors.affiliation: Fujairah Hospital, Fujairah, United Arab Emirates.
authors.forename: Olfat
authors.initials: O
authors.lastname: Al-Zaabi
authors.affiliation: Mafraq Hospital, Abu Dhabi, United Arab Emirates.
authors.forename: Waseem
authors.initials: W
authors.lastname: Fathallah
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Baylor Miraca Genetics Laboratories, Houston, TX 77030, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Cui
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Baylor Miraca Genetics Laboratories, Houston, TX 77030, USA.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Baylor Miraca Genetics Laboratories, Houston, TX 77030, USA.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Eng
authors.affiliation: College of Pharmacy, Al Ain University of Science and Technology, Al-Ain, United Arab Emirates.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Al Sorkhy
authors.affiliation: College of Pharmacy, Al Ain University of Science and Technology, Al-Ain, United Arab Emirates.
authors.forename: Mohammad A
authors.initials: MA
authors.lastname: Ghattas
authors.affiliation: Department of Paediatrics, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates.
authors.forename: Lihadh
authors.initials: L
authors.lastname: Al-Gazali
authors.affiliation: Department of Pathology, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates. Electronic address: bassam.ali@uaeu.ac.ae.
authors.forename: Bassam R
authors.initials: BR
authors.lastname: Ali
mesh_terms: D020134:Catalytic Domain; D002453:Cell Cycle; D049109:Cell Proliferation; D002675:Child, Preschool; D018360:Crystallography, X-Ray; D004200:Diseases in Twins; D059472:Exome; D005192:Family Health; D005220:Fathers; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D058627:Megalencephaly / Q000235:genetics*; D009035:Mothers; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D014430:Twins, Monozygotic; D054462:p21-Activated Kinases / Q000235:genetics*
chemical_list: C515911:PAK3 protein, human; D054462:p21-Activated Kinases
keywords: Intellectual disability; Macrocephaly; PAK3; X-linked; de novo mutation