The landscape of autosomal-recessive pathogenic variants in European populations reveals phenotype-specific effects

Fridman, Hila; Yntema, Helger G.; Mägi, Reedik; Andreson, Reidar; Metspalu, Andres; Mezzavila, Massimo; Tyler‐Smith, Chris; Xue, Yali; Carmi, Shai; Levy‐Lahad, Ephrat; Gilissen, Christian; Brunner, Han G.

doi:10.1016/j.ajhg.2021.03.004

Cited by 51 publications

(45 citation statements)

References 46 publications

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“…These estimates are compatible with the calculation that couples who are first cousins show an extra 2-3% increased risk of having children with AR genetic problems (Hamamy et al, 2011). As expected, the risks gradually decreased for more distant relationships and the risk for third cousins was similar to that for non-consanguineous couples (Fridman et al, 2021).…”

Section: Introductionsupporting

confidence: 88%

“…If we limit our analysis to the 25 first cousin couples, we can observe that 13 of them (52%) have one or more shared pathogenic or likely pathogenic (PLP) variant. Although 26 couples are not a large number, this percentage is more than double the rate of 20.9–24.9% at risk couples (ARC) estimated by Fridman et al (2021) for first cousins, based on simulated consanguineous matings. We can derive mathematically the relationship of the rate of ARCs to the PLPs for a given CGR with the formula:…”

Section: Resultsmentioning

confidence: 86%

“…However, to offer effective pre-conceptive screening for consanguineous couples it is not necessary to identify all the pathogenic variants for which each member of a couple is a carrier, being sufficient to identify only which pathogenic variants are shared by them. Fridman et al (2021) studied 6,447 exome sequences of healthy, genetically unrelated Europeans from Holland and Estonia and calculated that almost all individuals (>85%) carry at least one pathogenic or likely pathogenic (PLP) variant, with an average of at least 1.3 PLPs for a severe AR disorder and 2.2 PLPs for any AR disorder. Their data did not allow estimation of the upper bound, but they felt it unlikely that the number of PLPs would exceed 8 per individual.…”

Section: Introductionmentioning

confidence: 99%

“… Fridman et al (2021) studied 6,447 exome sequences of healthy, genetically unrelated Europeans from Holland and Estonia and calculated that almost all individuals (>85%) carry at least one pathogenic or likely pathogenic (PLP) variant, with an average of at least 1.3 PLPs for a severe AR disorder and 2.2 PLPs for any AR disorder. Their data did not allow estimation of the upper bound, but they felt it unlikely that the number of PLPs would exceed 8 per individual.…”

Section: Introductionmentioning

confidence: 99%

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A Protocol for Preconceptional Screening of Consanguineous Couples Using Whole Exome Sequencing

Santos¹,

Heller²,

Pena³

et al. 2021

Front. Genet.

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Genetic studies performed in consanguineous couples suggest that the reproductive risk that distinguish them from other couples in the general population is related to autosomal recessive (AR) diseases. This risk is scattered among the thousands of known and potential AR diseases. Thus, for effective preconceptional screening of consanguineous couples it is necessary a test that encompasses the largest number of genes possible. For that reason, we decided to create a protocol based on whole exome sequencing (WES). We sequenced completely the exomes of 39 consanguineous couples at high coverage (∼100×). Applying bioinformatics filters, we could detect genetic variants that were simultaneously present in both members of the couple in all genes listed in the Clinical Genomics Database as causally related to AR diseases. Shared variants were then assessed for pathogenicity. For non-truncating variants (missense and in-frame indels) we considered as pathogenic or likely pathogenic only the variants included as such in the ClinVar database. Shared truncating variants (frameshift, non-sense, and canonical splice variants) were considered likely pathogenic when loss-of-function was a known mechanism of disease. The 39 consanguineous cases included two couples with a coefficient of genetic relationship (CGR) of 0.25, 26 couples with a CGR of 0.125, three couples with a CGR of 0.0625 and eight couples with a CGR of 0.03125. In 21 of the 39 couples (53.8%) we ascertained sharing of heterozygosity for at least one variant considered pathogenic or likely pathogenic for an AR disease. In eight couples we found sharing of heterozygosity for at least two pathogenic variants. Once the specific pathogenic variant was identified, it became possible for the couple to undergo prenatal diagnosis or, if desired, preimplantation genetic diagnosis (PGD) involving in vitro fertilization and embryo screening. In conclusion, our results demonstrate that preconceptional screening by WES is a useful new procedure that should be incorporated in the genetic counseling of all consanguineous couples.

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Section: Introductionsupporting

confidence: 88%

Section: Resultsmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A Protocol for Preconceptional Screening of Consanguineous Couples Using Whole Exome Sequencing

Santos¹,

Heller²,

Pena³

et al. 2021

Front. Genet.

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show abstract

“…Whilst most AR conditions are rare, it is thought that everyone is a carrier of an average of 2.8 severe AR conditions (15) and, when mild ones are included this number increases to over 20 conditions (14). The chances of being a carrier couple for an AR condition are approximately 1% depending on the ethnic composition of the population or whether any founding effects are present (19)(20)(21) and the chances of being a carrier couple for a limited set of severe AR conditions, such as those included in the UMCG test discussed in this thesis (for more details see section 1.2.4), are estimated to be 1 in 150 in the Dutch general population (19,22). This is comparable to the (average) risk of having a child with Down's syndrome for which prenatal screening is routinely offered (23).…”

Section: Introducing the Topic Of This Phd Researchmentioning

confidence: 99%

Population-based Expanded Carrier Screening reporting couple results only: a mixed methods approach

Schuurmans¹

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Estimation of carrier frequencies utilizing the gnomAD database for ACMG recommended carrier screening and Finnish disease heritage conditions in non‐Finnish European, Finnish, and Ashkenazi Jewish populations

Kandolin,

Pöyhönen,

Jakkula

2024

American J of Med Genetics Pt A

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American College of Medical Genetics and Genomics (ACMG) recommends offering Tier 3 carrier screening to pregnant patients and those planning a pregnancy for conditions with a carrier frequency of ≥1/200 (96 genes for autosomal recessive [AR] conditions). Certain AR conditions referred to as Finnish disease heritage (FINDIS) have a higher prevalence in Finland than elsewhere. Data from gnomAD v2.1 were extracted to assess carrier frequencies for ACMG‐recommended AR and FINDIS AR and X‐linked genes in Finnish, non‐Finnish European, and Ashkenazi Jewish populations. Following variants were considered: ClinVar pathogenic or likely pathogenic, loss‐of‐function, and Finnish founder variants. Gene carrier (GCR), cumulative carrier (CCR), and at‐risk couple rates (ACR) were estimated. In Finnish population, 47 genes had a GCR of ≥0.5%. CCRs were 52.7% (Finnish), 48.9% (non‐Finnish European), and 58.3% (Ashkenazi Jewish), whereas ACRs were 1.4%, 0.93%, and 2.3% respectively. Approximately 141 affected children with analyzed AR conditions are estimated to be born in Finland annually. Eighteen genes causing FINDIS conditions had a GCR of ≥0.5% in the Finnish population but were absent in the ACMG Tier 3 gene list. Two genes (RECQL4 and RMRP) had GCR of ≥0.5% either in non‐Finnish Europeans or Ashkenazi Jewish populations. Results highlight the need for careful curation of carrier screening panels.

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The landscape of autosomal-recessive pathogenic variants in European populations reveals phenotype-specific effects

Cited by 51 publications

References 46 publications

A Protocol for Preconceptional Screening of Consanguineous Couples Using Whole Exome Sequencing

A Protocol for Preconceptional Screening of Consanguineous Couples Using Whole Exome Sequencing

Population-based Expanded Carrier Screening reporting couple results only: a mixed methods approach

Estimation of carrier frequencies utilizing the gnomAD database for ACMG recommended carrier screening and Finnish disease heritage conditions in non‐Finnish European, Finnish, and Ashkenazi Jewish populations

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