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. European Journal of Human Genetics (2013) 21, 229-232; doi:10.1038/ejhg.2012.79; published online 2 May 2012
TRAPPC9-related autosomal recessive intellectual disability: report of a new mutation and clinical phenotype / Giuseppe, Marangi; Leuzzi, Vincenzo; Manti, Filippo; Serena, Lattante; Daniela, Orteschi; Vanna, Pecile; Giovanni, Neri; Marcella, Zollino. - In: EUROPEAN JOURNAL OF HUMAN GENETICS. - ISSN 1018-4813. - ELETTRONICO. - 21:2(2013), pp. 229-232. [10.1038/ejhg.2012.79]
TRAPPC9-related autosomal recessive intellectual disability: report of a new mutation and clinical phenotype
LEUZZI, Vincenzo;MANTI, FILIPPO;
2013
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. European Journal of Human Genetics (2013) 21, 229-232; doi:10.1038/ejhg.2012.79; published online 2 May 2012I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.