title: Exome sequencing discloses KALRN homozygous variant as likely cause of intellectual disability and short stature in a consanguineous pedigree.
abstract: The recent availability of whole-exome sequencing has opened new possibilities for the evaluation of individuals with genetically undiagnosed intellectual disability.
  
  
  
  We report two affected siblings, offspring of first-cousin parents, with intellectual disability, hypotonia, short stature, growth hormone deficiency, and delayed bone age. All members of the nuclear family were genotyped, and exome sequencing was performed in one of the affected individuals. We used an in-house algorithm (CATCH v1.1) that combines homozygosity mapping with exome sequencing results and provides a list of candidate variants. One identified novel homozygous missense variant in KALRN (NM_003947.4:c.3644C>A: p.(Thr1215Lys)) was predicted to be pathogenic by all pathogenicity prediction software used (SIFT, PolyPhen, Mutation Taster). KALRN encodes the protein kalirin, which is a GTP-exchange factor protein with a reported role in cytoskeletal remodeling and dendritic spine formation in neurons. It is known that mice with ablation of Kalrn exhibit age-dependent functional deficits and behavioral phenotypes.
  
  
  
  Exome sequencing provided initial evidence linking KALRN to monogenic intellectual disability in man, and we propose that KALRN is the causative gene for the autosomal recessive phenotype in this family.
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva, 1 Rue Michel-Servet, 1211, Geneva, Switzerland.|Service of Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland.
authors.forename: Periklis
authors.initials: P
authors.lastname: Makrythanasis
authors.affiliation: Service of Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland.
authors.forename: Michel
authors.initials: M
authors.lastname: Guipponi
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva, 1 Rue Michel-Servet, 1211, Geneva, Switzerland.
authors.forename: Federico A
authors.initials: FA
authors.lastname: Santoni
authors.affiliation: Department of Clinical Genetics, National Research Centre, Cairo, Egypt.
authors.forename: Maha
authors.initials: M
authors.lastname: Zaki
authors.affiliation: Department of Clinical Genetics, National Research Centre, Cairo, Egypt.
authors.forename: Mahmoud Y
authors.initials: MY
authors.lastname: Issa
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva, 1 Rue Michel-Servet, 1211, Geneva, Switzerland.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ansar
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva, 1 Rue Michel-Servet, 1211, Geneva, Switzerland. hananhamamy@yahoo.com.
authors.forename: Hanan
authors.initials: H
authors.lastname: Hamamy
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva, 1 Rue Michel-Servet, 1211, Geneva, Switzerland. Stylianos.Antonarakis@unige.ch.|Service of Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland. Stylianos.Antonarakis@unige.ch.|iGE3, Institute of Genetics and Genomics of Geneva, Geneva, Switzerland. Stylianos.Antonarakis@unige.ch.
authors.forename: Stylianos E
authors.initials: SE
authors.lastname: Antonarakis
mesh_terms: D000293:Adolescent; D002648:Child; D003241:Consanguinity; D004252:DNA Mutational Analysis; D002658:Developmental Disabilities / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*
chemical_list: D020662:Guanine Nucleotide Exchange Factors; C503866:KALRN protein, human; D017346:Protein Serine-Threonine Kinases
keywords: Consanguineous; Exome sequencing; Intellectual disability; KALRN; Short stature