title: TRAPPC9-related autosomal recessive intellectual disability: report of a new mutation and clinical phenotype.
abstract: Intellectual disability (ID) with autosomal recessive (AR) inheritance is believed to be common; however, very little is known about causative genes and genotype-phenotype correlations. The broad genetic heterogeneity of AR-ID, and its usually nonsyndromic nature make it difficult to pool multiple pedigrees with the same underlying genetic defect to achieve consistent nosology. Nearly all autosomal genes responsible for recessive cognitive disorders have been identified in large consanguineous families from the Middle East, and nonsense mutations in TRAPPC9 have been reported in a total of 5. Although several recurrent phenotypic abnormalities are described in some of these patients, the associated phenotype is usually referred to as nonsyndromic. By means of single-nucleotide polymorphism-array first and then by exome sequencing, we identified a new pathogenic mutation in TRAPPC9 in two Italian sisters born to healthy and apparently nonconsanguineous parents. It consists of a homozygous splice site mutation causing exon skipping with frameshift and premature termination, as confirmed by mRNA sequencing. By detailed phenotypic analysis of our patients, and by critical literature review, we found that homozygous TRAPPC9 loss-of-function mutations cause a distinctive phenotype, characterized by peculiar facial appearance, obesity, hypotonia (all signs resembling a Prader-Willi-like phenotype), moderate-to-severe ID, and consistent brain abnormalities.
authors.affiliation: Istituto di Genetica Medica, Università Cattolica Sacro Cuore, Largo Francesco Vito 1, Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Marangi
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Leuzzi
authors.forename: Filippo
authors.initials: F
authors.lastname: Manti
authors.forename: Serena
authors.initials: S
authors.lastname: Lattante
authors.forename: Daniela
authors.initials: D
authors.lastname: Orteschi
authors.forename: Vanna
authors.initials: V
authors.lastname: Pecile
authors.forename: Giovanni
authors.initials: G
authors.lastname: Neri
authors.forename: Marcella
authors.initials: M
authors.lastname: Zollino
mesh_terms: D002352:Carrier Proteins / Q000235:genetics*; D003241:Consanguinity; D005091:Exons; D005808:Genes, Recessive; D056726:Genetic Association Studies; D006720:Homozygote; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics / Q000503:physiopathology; D036341:Intercellular Signaling Peptides and Proteins; D008877:Middle East; D009154:Mutation; D009765:Obesity / Q000235:genetics / Q000503:physiopathology; D010375:Pedigree; D011218:Prader-Willi Syndrome / Q000235:genetics / Q000503:physiopathology
chemical_list: D002352:Carrier Proteins; D036341:Intercellular Signaling Peptides and Proteins; C503887:TRAPPC9 protein, human