Clinical characterization, genetic mapping and whole-genome sequence analysis of a novel autosomal recessive intellectual disability syndrome

Eur J Med Genet. 2014 Oct;57(10):543-51. doi: 10.1016/j.ejmg.2014.07.002. Epub 2014 Jul 29.


We identified six patients presenting with a strikingly similar clinical phenotype of profound syndromic intellectual disability of unknown etiology. All patients lived in the same village. Extensive genealogical work revealed that the healthy parents of the patients were all distantly related to a common ancestor from the 17th century, suggesting autosomal recessive inheritance. In addition to intellectual disability, the clinical features included hypotonia, strabismus, difficulty to fix the eyes to an object, planovalgus in the feet, mild contractures in elbow joints, interphalangeal joint hypermobility and coarse facial features that develop gradually during childhood. The clinical phenotype did not fit any known syndrome. Genome-wide SNP genotyping of the patients and genetic mapping revealed the longest shared homozygosity at 3p22.1-3p21.1 encompassing 11.5 Mb, with no other credible candidate loci emerging. Single point parametric linkage analysis showed logarithm of the odds score of 11 for the homozygous region, thus identifying a novel intellectual disability predisposition locus. Whole-genome sequencing of one affected individual pinpointed three genes with potentially protein damaging homozygous sequence changes within the predisposition locus: transketolase (TKT), prolyl 4-hydroxylase transmembrane (P4HTM), and ubiquitin specific peptidase 4 (USP4). The changes were found in heterozygous form with 0.3-0.7% allele frequencies in 402 whole-genome sequenced controls from the north-east of Finland. No homozygotes were found in this nor additional control data sets. Our study facilitates clinical and molecular diagnosis of patients with this novel autosomal recessive intellectual disability syndrome. However, further studies are needed to unambiguously identify the underlying genetic defect.

Keywords: Autosomal recessive; Consanguineous family; Homozygosity mapping; P4HTM; Profound syndromic intellectual disability; TKT; USP4; Whole-genome sequencing.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Chromosomes, Human, Pair 3*
  • DNA Mutational Analysis
  • Eye Abnormalities / genetics
  • Female
  • Finland
  • Genes, Recessive
  • Genetic Heterogeneity
  • Genotype
  • Humans
  • Intellectual Disability / genetics*
  • Male
  • Middle Aged
  • Muscle Hypotonia / genetics
  • Pedigree
  • Phenotype
  • Prolyl Hydroxylases / genetics
  • Sequence Analysis, DNA
  • Syndrome
  • Transketolase / deficiency
  • Transketolase / genetics
  • Ubiquitin Thiolesterase / genetics
  • Ubiquitin-Specific Proteases
  • Young Adult


  • USP4 protein, human
  • Prolyl Hydroxylases
  • Transketolase
  • Ubiquitin Thiolesterase
  • Ubiquitin-Specific Proteases