title: Isolated GH deficiency: mutation screening and copy number analysis of HMGA2 and CDK6 genes.
abstract: OBJECTIVE
  In most patients, the genetic cause of isolated GH deficiency (IGHD) is unknown. By identifying several genes associated with height variability within the normal population, three separate genome-wide association studies provided new candidate genes for human growth disorders. We selected two of them for genetic screening of our IGHD population.
  
  
  OBJECTIVE
  We aimed to determine whether high-mobility group A2 (HMGA2) and cyclin-dependent protein kinase 6 (CDK6) are involved in the pathogenicity of IGHD.
  
  
  METHODS
  We directly sequenced coding regions and exon-intron boundaries of the genes HMGA2 and CDK6 in 105 Caucasian IGHD patients from the Dutch HYPOPIT study. In addition, we developed a new probe set of multiplex ligation-dependent probe amplification for both genes in order to detect copy number variations.
  
  
  RESULTS
  In one patient with classical IGHD phenotype, we identified a new heterozygous 20 bp deletion in the intronic region of HMGA2 (c.250-29_-9del), which was absent in the databases and healthy controls. Together, with recently published data concerning the 12q14 microdeletion syndrome, where patients with an HMGA2 haploinsufficiency had proportionate short stature, this study provides further support of the important role for HMGA2 in growth. In CDK6, we found only known polymorphisms.
  
  
  CONCLUSIONS
  This study provides the first report of a deletion in the HMGA2 gene that might be related to IGHD. We suggest that this gene is investigated as a second screening in patients with a classical IGHD phenotype in which mutations in classical candidate genes have been excluded.
authors.affiliation: Pediatrics, Subdivision of Endocrinology, Erasmus University, Rotterdam, The Netherlands. d.gorbenkodelblanco@erasmusmc.nl
authors.forename: Darya
authors.initials: D
authors.lastname: Gorbenko del Blanco
authors.forename: Laura C G
authors.initials: LC
authors.lastname: de Graaff
authors.forename: Dirk
authors.initials: D
authors.lastname: Posthouwer
authors.forename: Theo J
authors.initials: TJ
authors.lastname: Visser
authors.forename: Anita C S
authors.initials: AC
authors.lastname: Hokken-Koelega
mesh_terms: D000293:Adolescent; D001827:Body Height / Q000235:genetics; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics*; D004247:DNA / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D018628:Gene Dosage; D055106:Genome-Wide Association Study; D005838:Genotype; D025743:HMGA2 Protein / Q000235:genetics*; D019382:Human Growth Hormone / Q000172:deficiency* / Q000235:genetics*; D006801:Humans; D007438:Introns / Q000235:genetics; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation; D009426:Netherlands; D010902:Pituitary Gland / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D044465:White People; D055815:Young Adult
chemical_list: D025743:HMGA2 Protein; D019382:Human Growth Hormone; D004247:DNA; C495911:CDK6 protein, human; D051361:Cyclin-Dependent Kinase 6