title: The alkylglycerol monooxygenase (AGMO) gene previously involved in autism also causes a novel syndromic form of primary microcephaly in a consanguineous Saudi family.
abstract: Autosomal recessive primary microcephaly (MCPH) refers to a genetically heterogeneous group of neurodevelopmental disorders in which patients exhibit a marked decrease in occipitofrontal head circumference at birth and a variable degree of intellectual disability. To date, 18 genes have been reported for MCPH worldwide. We enrolled a consanguineous family from Saudi Arabia presenting with primary microcephaly, developmental delay, short stature and intellectual disability. Whole exome sequencing (WES) with 100× coverage was performed on two affected siblings after defining common regions of homozygosity through genome-wide single nucleotide polymorphism (SNP) microarray genotyping. WES data analysis, confirmed by subsequent Sanger sequence validation, identified a novel homozygous deletion mutation (c.967delA; p.Glu324Lysfs12*) in exon 10 of the alkylglycerol monooxygenase (AGMO) gene on chromosome 7p21.2. Population screening of 178 ethnically matched control chromosomes and consultation of the Exome Aggregation Consortium database, containing 60,706 individuals' exomes worldwide, confirmed that this mutation was not present outside the family. To the best of our knowledge, this is the first evidence of an AGMO mutation underlying primary microcephaly and intellectual disability in humans. Our findings further expand the genetic heterogeneity of MCPH in familial cases.
authors.affiliation: Princess Al-Jawhara Albrahim Centre of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Saudi Arabia; Cell Sciences and Genetics Research Centre, St. George's University of London (SGUL), London SW17 0RE, United Kingdom.
authors.forename: Nuha
authors.initials: N
authors.lastname: Alrayes
authors.affiliation: Cell Sciences and Genetics Research Centre, St. George's University of London (SGUL), London SW17 0RE, United Kingdom.
authors.forename: Hussein Sheikh Ali
authors.initials: HS
authors.lastname: Mohamoud
authors.affiliation: Princess Al-Jawhara Albrahim Centre of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Saudi Arabia; Department of Genetic Medicine, King Abdulaziz University Hospital, Jeddah, Saudi Arabia.
authors.forename: Saleem
authors.initials: S
authors.lastname: Ahmed
authors.affiliation: Princess Al-Jawhara Albrahim Centre of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Saudi Arabia.
authors.forename: Mona Mohammad
authors.initials: MM
authors.lastname: Almramhi
authors.affiliation: Department of Paediatrics, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.
authors.forename: Taghreed Mohammad
authors.initials: TM
authors.lastname: Shuaib
authors.affiliation: Princess Al-Jawhara Albrahim Centre of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Saudi Arabia; BGI-Shenzhen, Shenzhen 518083, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Princess Al-Jawhara Albrahim Centre of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Saudi Arabia; Department of Genetic Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.
authors.forename: Jumana Yousuf
authors.initials: JY
authors.lastname: Al-Aama
authors.affiliation: Cell Sciences and Genetics Research Centre, St. George's University of London (SGUL), London SW17 0RE, United Kingdom.
authors.forename: Kate
authors.initials: K
authors.lastname: Everett
authors.affiliation: Cell Sciences and Genetics Research Centre, St. George's University of London (SGUL), London SW17 0RE, United Kingdom.
authors.forename: Jamal
authors.initials: J
authors.lastname: Nasir
authors.affiliation: Princess Al-Jawhara Albrahim Centre of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Saudi Arabia; Medical Genetics and Molecular Biology Unit, Biochemistry Department, Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, Pakistan. Electronic address: mjelani@kau.edu.sa.
authors.forename: Musharraf
authors.initials: M
authors.lastname: Jelani
mesh_terms: D000595:Amino Acid Sequence; D001321:Autistic Disorder / Q000235:genetics*; D001483:Base Sequence; D002648:Child; D003241:Consanguinity; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics; D008297:Male; D008831:Microcephaly / Q000175:diagnosis* / Q000235:genetics*; D006899:Mixed Function Oxygenases / Q000235:genetics*; D010375:Pedigree; D012529:Saudi Arabia
chemical_list: D006899:Mixed Function Oxygenases; C020678:glyceryl-ether monooxygenase
keywords: Alkylglycerol monooxygenase; Autosomal recessive primary microcephaly; Frameshift deletion mutation; Novel homozygous; Saudi Arabia; Whole exome sequencing