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Carrier screening for recessive disorders


Technological and other advances over the past decades have led to the discovery of thousands of gene–disease associations for autosomal and X-linked recessive Mendelian disorders. Combined with recent improvements in assessing individual variants in each human genome, these developments offer the possibility of testing populations for all known severe recessive genetic disorders. Past experience has provided the framework for expanded carrier screening, but many challenges remain regarding which disorders to include, how to interpret variants and how to incorporate newly discovered gene–disease links into existing screening programmes.

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The author thanks I. Kolpakov, M. Garieri, M. Ansar, E. Ranza, T. Papayannopoulou and H. C. Martin for discussions or preparation of figures, and the University of Geneva for continuous support. The author also thanks the three anonymous expert reviewers for their constructive comments.

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Correspondence to Stylianos E. Antonarakis.

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Clinical Genomic Database (CGD):

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Consanguinity and endogamy resource:

Cystic Fibrosis Mutation Database:

Dor Yeshorim:

Exome Aggregation Consortium (ExAC) browser:

Genome Aggregation Database (gnomAD):

gnomAD 7-117171028-C-T:

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Online Mendelian Inheritance in Man (OMIM):

The American College of Medical Genetics and Genomics (ACMG):

The American College of Obstetricians and Gynecologists (ACOG):

The European Society of Human Genetics (ESHG) Public and Professional Policy Committee:

This Review is dedicated to the memory of Professor George Stamatoyannopoulos (1934–2018).

Supplementary information

Supplementary Information


Autosomal recessive inheritance

The mode of inheritance in which the phenotype is due to two pathogenic variants in the same gene: one in the paternal allele and the other in the maternal allele. The causative gene maps in one of the autosomes.

Carrier screening

The detection of unaffected individuals who harbour one copy of a pathogenic variant in a gene known to be involved in a recessive disorder.

X-linked disorders

Genetic disorders for which the pathogenic variant is on the X chromosome.

Expanded carrier screening

(ECS). Genetic testing for a large number of genetic disorders (generally 100 or more) simultaneously in 1 test. In this Review, ECS refers to the identification of carriers for the majority of severe Mendelian autosomal recessive and X-linked disorders beyond the traditional screening guidelines.


A term that refers to the practice of marrying within a specific social or ethnic community or otherwise closed population.


Mating among close relatives, for example, first or second cousins.


Also known as identity by descent. The inheritance of two alleles at a locus from a common ancestor due to inbreeding.

Founder effects

The loss of genetic variation when a new population is established by a very small number of individuals from a larger population.

Variable expressivity

A phenotype expressed to a different degree among individuals with the same genotype.


The fraction of individuals with a phenotype given a genotype known to cause a disease.

Compound heterozygosity

The condition of having two different pathogenic recessive variants, one in each parental allele, at a particular locus.

Copy number variants

(CNVs). Genomic variation due to different copies of a sequence in different alleles.

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Fig. 1: Haploinsufficiency index for autosomal recessive and dominant genes.
Fig. 2: The Ptolemy dynasty, 323–30 bce.
Fig. 3: Likelihood of autosomal recessive disorders.
Fig. 4: Homozygosity regions in the genomes of outbred and inbred individuals.
Fig. 5: Potential different thresholds for the interpretation of variants of recessive genes in expanded carrier screening.