title: Exome analysis identified a novel missense mutation in the CLPP gene in a consanguineous Saudi family expanding the clinical spectrum of Perrault Syndrome type-3.
abstract: Perrault syndrome (PRLTS) is a clinically and genetically heterogeneous disorder. Both male and female patients suffer from sensory neuronal hearing loss in early childhood, and female patients are characterized by premature ovarian failure and infertility after puberty. Clinical diagnosis may not be possible in early life, because key features of PRLTS, for example infertility and premature ovarian failure, do not appear before puberty. Limb spasticity, muscle weakness, and intellectual disability have also been observed in PRLTS patients. Mutations in five genes, HSD17B4, HARS2, CLPP, LARS2, and C10orf2, have been reported in five subtypes of PRLTS. We discovered a consanguineous Saudi family with the PRLTS3 phenotype showing an autosomal recessive mode of inheritance. The patients had developed profound hearing loss, brain atrophy, and lower limb spasticity in early childhood. For molecular diagnosis, we complimented genome-wide homozygosity mapping with whole exome sequencing analyses and identified a novel homozygous mutation in exon 6 of CLPP at chromosome 19p13.3. To our knowledge, early onset with regression is a unique feature of these PRLTS patients that has not been reported so far. This study broadens the clinical spectrum of PRLTS3.
authors.affiliation: Princess Al-Jawhara Albrahim Center 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: Saleem
authors.initials: S
authors.lastname: Ahmed
authors.affiliation: Princess Al-Jawhara Albrahim Center 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; Human Genetics Research Centre, Division of Biomedical Sciences (BMS), St. George's University of London (SGUL), London SW17 0RE, United Kingdom. Electronic address: mjelani@kau.edu.sa.
authors.forename: Musharraf
authors.initials: M
authors.lastname: Jelani
authors.affiliation: Human Genetics Research Centre, Division of Biomedical Sciences (BMS), St. George's University of London (SGUL), London SW17 0RE, United Kingdom.
authors.forename: Nuha
authors.initials: N
authors.lastname: Alrayes
authors.affiliation: Princess Al-Jawhara Albrahim Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Saudi Arabia; Human Genetics Research Centre, Division of Biomedical Sciences (BMS), 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 Center 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 Pediatrics, King Abdulaziz University Hospital, Jeddah, Saudi Arabia.
authors.forename: Wasim
authors.initials: W
authors.lastname: Anshasi
authors.affiliation: Department of Radiology, King Abdulaziz University Hospital, Jeddah, Saudi Arabia.
authors.forename: Naushad Ali Basheer
authors.initials: NA
authors.lastname: Ahmed
authors.affiliation: Princess Al-Jawhara Albrahim Center 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: Human Genetics Research Centre, Division of Biomedical Sciences (BMS), 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 Center 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
mesh_terms: D001921:Brain / Q000473:pathology; D002648:Child; D002869:Chromosome Aberrations; D003241:Consanguinity; D004252:DNA Mutational Analysis; D049071:Endopeptidase Clp / Q000235:genetics*; D005192:Family Health; D005260:Female; D023961:Gonadal Dysgenesis, 46,XX / Q000235:genetics* / Q000473:pathology; D006319:Hearing Loss, Sensorineural / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D020125:Mutation, Missense / Q000235:genetics*; D010641:Phenotype; D015203:Reproducibility of Results; D012529:Saudi Arabia / Q000453:epidemiology
chemical_list: C568646:ClpP protein, human; D049071:Endopeptidase Clp
keywords: Brain atrophy; CLPP; Novel homozygous mutation; Perrault syndrome type 3; Saudi Arabia; Whole-exome sequencing