Truncating Neurotrypsin Mutation in Autosomal Recessive Nonsyndromic Mental Retardation

Molinari, Florence; Rio, Marlène; Meskenaïte, Virginia; Encha‐Razavi, Férechté; Augé, Jordan; Bacq, Delphine; Briault, Sylvain; Vekemans, Michel; Münnich, Arnold; Attié‐Bitach, Tania; Sonderegger, P.; Colleaux, Laurence

doi:10.1126/science.1076521

Cited by 174 publications

(170 citation statements)

References 26 publications

Supporting

Mentioning

161

Contrasting

Order By: Relevance

“…[1][2][3] Few autosomal recessive (AR) genes and several other loci have been identified by means of linkage analysis and genome-wide homozigosity mapping in large consanguineous families followed by resenquencing of candidate genes. These include PRSS12 (MIM 606709), 4 CRBN (MIM 609262), 5 CC2D1A (MIM 610055), 6 GRIK2 (MIM 138244), 7 TUSC3 (MIM 601385), 8,9 and TRAPPC9 (MIM 611966). [10][11][12][13] The introduction of next generation sequencing techniques dramatically changed this scenario, leading to the discovery of a rapidly increasing number of AR-NSID causative genes.…”

Section: Introductionmentioning

confidence: 99%

TRAPPC9-related autosomal recessive intellectual disability: report of a new mutation and clinical phenotype

et al. 2012

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

confidence: 99%

TRAPPC9-related autosomal recessive intellectual disability: report of a new mutation and clinical phenotype

et al. 2012

View full text Add to dashboard Cite

show abstract

“…6 Until now, 26 significantly linked non-specific intellectual disability of autosomal recessive inheritance (NS-ARID) loci were described, [7][8][9][10] and only 10 genes (six of them located in described regions) were identified: PRSS12 (OMIM#606709, on 4q26, former MRT1), CRBN (OMIM#609262, on 3p26, former MRT2), CC2D1A (OMIM#610055, on 19p13.12, former MRT3), ST3GAL3 (OMIM#606494, on 1p34.3), GRIK2 (OMIM#138277, on 6q16, former MRT6), TUSC3 (OMIM#601385, on 8p22, former MRT7), ZNF26 (no OMIM#, on 19q13.2), TRAPPC9 (OMIM#613192, on 8q24, former MRT13), ZCH14 (OMIM# 613279, on 14q31.3), and TECR (MIM*610057 on 19p13.12) (Figure 1). 1,[11][12][13][14][15][16][17][18][19] Taking into account that over 90 genes are responsible for only about 40% of X-chromosomal recessive ID cases, and that about half of the estimated 22 000 human genes are expressed in the brain, the total number of ARID genes may run into the hundreds. 1 Considering the heterogeneity observed in previous linkage studies, and the fact that the so far identified genes do not account for a significant fraction of NS-ARID cases, systematic approaches are the most promising strategy to identify further genes.…”

Section: Introductionmentioning

confidence: 99%

Homozygosity mapping in 64 Syrian consanguineous families with non-specific intellectual disability reveals 11 novel loci and high heterogeneity

et al. 2011

View full text Add to dashboard Cite

Non-specific intellectual disability of autosomal recessive inheritance (NS-ARID) represents an important fraction of severe cognitive dysfunction disorders. To date, only 10 genes have been identified, and further 24 linked-ARID loci have been reported, as well as others with suggestive linkage. To discover novel genes causing NS-ARID, we undertook genome-wide homozygosity mapping in 64 consanguineous multiplex families of Syrian descent. A total of 11 families revealed unique, significantly linked loci at 4q26-4q28 (MRT17), 6q12-q15 (MRT18), 18p11 (MRT19), 16p12-q12 (MRT20), 11p15 (MRT21), 11p13-q14 (MRT23), 6p12 (MRT24), 12q13-q15 (MRT25), 14q11-q12 (MRT26), 15q23-q26 (MRT27), and 6q26-q27 (MRT28), respectively. Loci ranged between 1.2 and 45.6 Mb in length. One family showed linkage to chromosome 8q24.3, and we identified a mutation in TRAPPC9. Our study further highlights the extreme heterogeneity of NS-ARID, and suggests that no major disease gene is to be expected, at least in this study group. Systematic analysis of large numbers of affected families, as presented here, will help discovering the genetic causes of ID.

show abstract

“…5 -7 Only two autosomal genes, the PRSS12 gene on chromosome 4q26 [MIM 606709] and the CRBN gene on chromosome 3p26 [MIM 607417], have been shown to cause autosomal recessive NSMR, each gene in only one family. 8,9 Autosomal recessive diseases are common in the Arab population of Israel, mostly as a result of the high rate of consanguinity. Among Israeli Arabs, up to 44% of the marriages used to be between relatives, approximately half of which were between first cousins, although these numbers are somewhat lower today.…”

Section: Introductionmentioning

confidence: 99%

Genetic screening for autosomal recessive nonsyndromic mental retardation in an isolated population in Israel

et al. 2006

View full text Add to dashboard Cite

Nonsyndromic mental retardation (NSMR) is the diagnosis of exclusion in mentally retarded individuals without additional abnormalities. We have recently identified a protein-truncating mutation, G408fsX437, in the gene CC2D1A on chromosome 19p13.12 in nine consanguineous Israeli Arab families with severe autosomal recessive NSMR, and have developed a comprehensive prevention program among the at-risk population in the village. The subjects tested were healthy women who were invited to undergo the genetic screening test as a part of their routine pregnancy monitoring. One hundred and seventeen subjects reported a family history positive for mental retardation. We tested 524 pregnant or preconceptional women and found 47 carriers (B1/11), whose spouses were then recommended to undergo testing. We identified eight carrier couples, who were given genetic counseling and offered prenatal diagnosis. Of all the marriages, 28.6% were consanguineous; 16.5% of the total were between first cousins. The high prevalence of the mutation can be explained both by the founder effect owing to the generally high consanguinity rate among the inhabitants of the village, and also because two families with excessive numbers of mentally retarded offspring were unacceptable as marriage partners by the rest of the families. This is the first example of the establishment of a large-scale genetic screening program for autosomal recessive NSMR, which was made possible owing to the high frequency of the specific causative mutation in this isolated population.

show abstract

Truncating Neurotrypsin Mutation in Autosomal Recessive Nonsyndromic Mental Retardation

Cited by 174 publications

References 26 publications

TRAPPC9-related autosomal recessive intellectual disability: report of a new mutation and clinical phenotype

TRAPPC9-related autosomal recessive intellectual disability: report of a new mutation and clinical phenotype

Homozygosity mapping in 64 Syrian consanguineous families with non-specific intellectual disability reveals 11 novel loci and high heterogeneity

Genetic screening for autosomal recessive nonsyndromic mental retardation in an isolated population in Israel

Contact Info

Product

Resources

About