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The genetic and molecular analyses of RAD51C and RAD51D identifies rare variants implicated in hereditary ovarian cancer from a genetically unique population
Simple SummaryWe have investigated RAD51C and RAD51D, hereditary ovarian cancer risk genes, in French Canadians of Quebec, Canada. This population of Western European origins exhibits a unique genetic landscape as shown by the frequency of carriers of specific rare pathogenic variants. As studying French Canadians could facilitate the identification and interpretation of clinically relevant variants, we performed genetic analyses of RAD51C and RAD51D in this population comprised of cases with a family history of ovarian cancer or those who developed it at a young age. We identified candidate variants and then investigated them in other French Canadian study groups. We performed biological assays and revealed possible mechanisms that would affect gene function. Using engineered cells expressing one of our protein variants, we also showed that they were more sensitive to a recently approved treatment for ovarian cancer. Our findings support the role of inherited variants in RAD51C and RAD51D in ovarian cancer.AbstractTo identify candidate variants in RAD51C and RAD51D ovarian cancer (OC) predisposing genes by investigating French Canadians (FC) exhibiting unique genetic architecture. Candidates were identified by whole exome sequencing analysis of 17 OC families and 53 early-onset OC cases. Carrier frequencies were determined by the genetic analysis of 100 OC or HBOC families, 438 sporadic OC cases and 1025 controls. Variants of unknown function were assayed for their biological impact and/or cellular sensitivity to olaparib. RAD51C c.414G>C;p.Leu138Phe and c.705G>T;p.Lys235Asn and RAD51D c.137C>G;p.Ser46Cys, c.620C>T;p.Ser207Leu and c.694C>T;p.Arg232Ter were identified in 17.6% of families and 11.3% of early-onset cases. The highest carrier frequency was observed in OC families (1/44, 2.3%) and sporadic cases (15/438, 3.4%) harbouring RAD51D c.620C>T versus controls (1/1025, 0.1%). Carriers of c.620C>T (n = 7), c.705G>T (n = 2) and c.137C>G (n = 1) were identified in another 538 FC OC cases. RAD51C c.705G>T affected splicing by skipping exon four, while RAD51D p.Ser46Cys affected protein stability and conferred olaparib sensitivity. Genetic and functional assays implicate RAD51C c.705G>T and RAD51D c.137C>G as likely pathogenic variants in OC. The high carrier frequency of RAD51D c.620C>T in FC OC cases validates previous findings. Our findings further support the role of RAD51C and RAD51D in hereditary OC.</p
Pairwise linkage disequilibrium (LD) diagram for <i>CPT1B</i> and <i>CPT2</i> in Inuit.
<p>LD block was delineated using confidence intervals (Gabriel et al), and 0.6–0.98 for strong LD. Variants of MAF<0.05 were indicated with dashed-line. Variants were extracted from exome sequencing and SNP array data, with the asterisk indicated variants only genotyped by the SNP array. D value <1 was shown in the box, with red color indicated LOD ≥2.</p
Mutation burden scores of identified rare mutations (MAF<0.01) of carnitine acyltransferase genes in Nunavik Inuit and 1KGP Asians.
<p>Mutation burden scores of identified rare mutations (MAF<0.01) of carnitine acyltransferase genes in Nunavik Inuit and 1KGP Asians.</p
Genomic features of carnitine acyltransferase genes.
<p>Genomic features of carnitine acyltransferase genes.</p
Coding variants of carnitine acyltransferase genes discovered in Nunavik Inuit.
<p>Coding variants of carnitine acyltransferase genes discovered in Nunavik Inuit.</p
The <i>F</i><sub><i>ST</i></sub> and <i>F</i><sub><i>IS</i></sub> value of 13 variants in the population containing Nunavik Inuit and HapMap Asians.
<p>The <i>F</i><sub><i>ST</i></sub> and <i>F</i><sub><i>IS</i></sub> value of 13 variants in the population containing Nunavik Inuit and HapMap Asians.</p
Scatterplot of the frequencies and deleterious scores of <i>CPT1A</i>, <i>CPT1B</i>, <i>CPT1C</i>, <i>CPT2</i> and <i>CRAT</i> missense variants.
<p>Variants were extracted from 286 Asians from 1KGP, EVS populations comprising 4,294 European descendants and 100 Nunavik Inuit.</p
Deleterious scores of all rare missense variants in carnitine acyltransferase genes found in Nunavik Inuit and 1KGP Asians.
<p>Deleterious scores of all rare missense variants in carnitine acyltransferase genes found in Nunavik Inuit and 1KGP Asians.</p
MDS plot showing the distinctive ethnicity relationships of CEU, YRI, JPT-CHB and Nunavik Inuit.
<p>Individuals in the dashed-line box have a mixture of both Inuit and European genomes.</p
<i>De Novo</i> Mutations in Moderate or Severe Intellectual Disability
<div><p>Genetics is believed to have an important role in intellectual disability (ID). Recent studies have emphasized the involvement of <i>de novo</i> 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 <i>de novo</i> 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 (<i>ARID1B, CHD2, FOXG1, GABRB3, GATAD2B, GRIN2B, MBD5, MED13L, SETBP1, TBR1, TCF4, WDR45</i>), resulting in a diagnostic yield of ∼29%. We also identified 12 possibly pathogenic DNMs in genes (<i>HNRNPU, WAC</i>, <i>RYR2, SET, EGR1, MYH10</i>, <i>EIF2C1</i>, <i>COL4A3BP, CHMP2A, PPP1CB, VPS4A, PPP2R2B</i>) 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.</p></div