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De novo mutations in moderate or severe intellectual disability.

Hamdan FF, Srour M, Capo-Chichi JM, Daoud H, Nassif C, Patry L, Massicotte C, Ambalavanan A, Spiegelman D, Diallo O, Henrion E, Dionne-Laporte A, Fougerat A, Pshezhetsky AV, Venkateswaran S, Rouleau GA, Michaud JL - PLoS Genet. (2014)

Bottom Line: A total of 12 likely pathogenic DNMs were identified in genes previously associated with ID (ARID1B, CHD2, FOXG1, GABRB3, GATAD2B, GRIN2B, MBD5, MED13L, SETBP1, TBR1, TCF4, WDR45), resulting in a diagnostic yield of ∼29%.Protein network analysis indicated that the products of many of these known and candidate genes interact with each other or with products of other ID-associated genes further supporting their involvement in ID.We conclude that DNMs represent a major cause of moderate or severe ID.

View Article: PubMed Central - PubMed

Affiliation: CHU Sainte-Justine Research Center, Montreal, Canada.

ABSTRACT
Genetics is believed to have an important role in intellectual disability (ID). Recent studies have emphasized the involvement of de novo mutations (DNMs) in ID but the extent to which they contribute to its pathogenesis and the identity of the corresponding genes remain largely unknown. Here, we report a screen for DNMs in subjects with moderate or severe ID. We sequenced the exomes of 41 probands and their parents, and confirmed 81 DNMs affecting the coding sequence or consensus splice sites (1.98 DNMs/proband). We observed a significant excess of de novo single nucleotide substitutions and loss-of-function mutations in these cases compared to control subjects, suggesting that at least a subset of these variations are pathogenic. A total of 12 likely pathogenic DNMs were identified in genes previously associated with ID (ARID1B, CHD2, FOXG1, GABRB3, GATAD2B, GRIN2B, MBD5, MED13L, SETBP1, TBR1, TCF4, WDR45), resulting in a diagnostic yield of ∼29%. We also identified 12 possibly pathogenic DNMs in genes (HNRNPU, WAC, RYR2, SET, EGR1, MYH10, EIF2C1, COL4A3BP, CHMP2A, PPP1CB, VPS4A, PPP2R2B) that have not previously been causally linked to ID. Interestingly, no case was explained by inherited mutations. Protein network analysis indicated that the products of many of these known and candidate genes interact with each other or with products of other ID-associated genes further supporting their involvement in ID. We conclude that DNMs represent a major cause of moderate or severe ID.

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Physical protein-protein interaction network generated by GeneMANIA (http://www.GeneMANIA.org/; Gene Ontology molecular function based weighting).The Query genes included those listed in Table 3 from this study (in bold) and known and candidate ID genes reported with predicted-damaging DNMs from other studies (Table S2). Known ID genes are in red. The resulting network of 38 interconnected proteins was found to be enriched for proteins whose Gene Ontology molecular functions are implicated in the glutamate receptor signalling pathway (GRIN1, GRIN2A, GRIN2B, GRIA1, CACNG2, SHANK3; FDR q-value = 7.04e-6).
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pgen-1004772-g002: Physical protein-protein interaction network generated by GeneMANIA (http://www.GeneMANIA.org/; Gene Ontology molecular function based weighting).The Query genes included those listed in Table 3 from this study (in bold) and known and candidate ID genes reported with predicted-damaging DNMs from other studies (Table S2). Known ID genes are in red. The resulting network of 38 interconnected proteins was found to be enriched for proteins whose Gene Ontology molecular functions are implicated in the glutamate receptor signalling pathway (GRIN1, GRIN2A, GRIN2B, GRIA1, CACNG2, SHANK3; FDR q-value = 7.04e-6).

Mentions: Among the remaining cases, we also identified 6 predicted-damaging DNMs in genes (SET [OMIM 600960], EGR1 [OMIM 128990], PPP1CB [OMIM 600590], CHMP2A [OMIM 610893], PPP2R2B [OMIM 604325], and VPS4A [OMIM 609982]) that play biological functions relevant to ID (Table 2). Inspection of the EVS database revealed no LoF variants in these genes, with the exception of a single heterozygous variant in PPP1C1B (MAF = 1/12518) with a potential effect on splicing. In addition, some of these genes were found in proteomic studies to physically interact with the product of at least one ID-associated gene, further increasing the probability of their involvement in this disorder (see below and Figure 2). Each of these DNMs is discussed hereafter.


De novo mutations in moderate or severe intellectual disability.

Hamdan FF, Srour M, Capo-Chichi JM, Daoud H, Nassif C, Patry L, Massicotte C, Ambalavanan A, Spiegelman D, Diallo O, Henrion E, Dionne-Laporte A, Fougerat A, Pshezhetsky AV, Venkateswaran S, Rouleau GA, Michaud JL - PLoS Genet. (2014)

Physical protein-protein interaction network generated by GeneMANIA (http://www.GeneMANIA.org/; Gene Ontology molecular function based weighting).The Query genes included those listed in Table 3 from this study (in bold) and known and candidate ID genes reported with predicted-damaging DNMs from other studies (Table S2). Known ID genes are in red. The resulting network of 38 interconnected proteins was found to be enriched for proteins whose Gene Ontology molecular functions are implicated in the glutamate receptor signalling pathway (GRIN1, GRIN2A, GRIN2B, GRIA1, CACNG2, SHANK3; FDR q-value = 7.04e-6).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4214635&req=5

pgen-1004772-g002: Physical protein-protein interaction network generated by GeneMANIA (http://www.GeneMANIA.org/; Gene Ontology molecular function based weighting).The Query genes included those listed in Table 3 from this study (in bold) and known and candidate ID genes reported with predicted-damaging DNMs from other studies (Table S2). Known ID genes are in red. The resulting network of 38 interconnected proteins was found to be enriched for proteins whose Gene Ontology molecular functions are implicated in the glutamate receptor signalling pathway (GRIN1, GRIN2A, GRIN2B, GRIA1, CACNG2, SHANK3; FDR q-value = 7.04e-6).
Mentions: Among the remaining cases, we also identified 6 predicted-damaging DNMs in genes (SET [OMIM 600960], EGR1 [OMIM 128990], PPP1CB [OMIM 600590], CHMP2A [OMIM 610893], PPP2R2B [OMIM 604325], and VPS4A [OMIM 609982]) that play biological functions relevant to ID (Table 2). Inspection of the EVS database revealed no LoF variants in these genes, with the exception of a single heterozygous variant in PPP1C1B (MAF = 1/12518) with a potential effect on splicing. In addition, some of these genes were found in proteomic studies to physically interact with the product of at least one ID-associated gene, further increasing the probability of their involvement in this disorder (see below and Figure 2). Each of these DNMs is discussed hereafter.

Bottom Line: A total of 12 likely pathogenic DNMs were identified in genes previously associated with ID (ARID1B, CHD2, FOXG1, GABRB3, GATAD2B, GRIN2B, MBD5, MED13L, SETBP1, TBR1, TCF4, WDR45), resulting in a diagnostic yield of ∼29%.Protein network analysis indicated that the products of many of these known and candidate genes interact with each other or with products of other ID-associated genes further supporting their involvement in ID.We conclude that DNMs represent a major cause of moderate or severe ID.

View Article: PubMed Central - PubMed

Affiliation: CHU Sainte-Justine Research Center, Montreal, Canada.

ABSTRACT
Genetics is believed to have an important role in intellectual disability (ID). Recent studies have emphasized the involvement of de novo mutations (DNMs) in ID but the extent to which they contribute to its pathogenesis and the identity of the corresponding genes remain largely unknown. Here, we report a screen for DNMs in subjects with moderate or severe ID. We sequenced the exomes of 41 probands and their parents, and confirmed 81 DNMs affecting the coding sequence or consensus splice sites (1.98 DNMs/proband). We observed a significant excess of de novo single nucleotide substitutions and loss-of-function mutations in these cases compared to control subjects, suggesting that at least a subset of these variations are pathogenic. A total of 12 likely pathogenic DNMs were identified in genes previously associated with ID (ARID1B, CHD2, FOXG1, GABRB3, GATAD2B, GRIN2B, MBD5, MED13L, SETBP1, TBR1, TCF4, WDR45), resulting in a diagnostic yield of ∼29%. We also identified 12 possibly pathogenic DNMs in genes (HNRNPU, WAC, RYR2, SET, EGR1, MYH10, EIF2C1, COL4A3BP, CHMP2A, PPP1CB, VPS4A, PPP2R2B) that have not previously been causally linked to ID. Interestingly, no case was explained by inherited mutations. Protein network analysis indicated that the products of many of these known and candidate genes interact with each other or with products of other ID-associated genes further supporting their involvement in ID. We conclude that DNMs represent a major cause of moderate or severe ID.

Show MeSH
Related in: MedlinePlus