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Whole Exome Sequencing Is the Minimal Technological Approach in Probands Born to Consanguineous Couples.

ABSTRACT: We report on two siblings suffering from different pathogenic conditions, born to consanguineous parents. A multigene panel for brain malformations and microcephaly identified the homozygous splicing variant NM_005886.3:c.1416+1del in the KATNB1 gene in the older sister. On the other hand, exome sequencing revealed the homozygous frameshift variant NM_005245.4:c.9729del in the FAT1 gene in the younger sister, who had a more complex phenotype: in addition to bilateral anophthalmia and heart defects, she showed a right split foot with 4 toes, 5 metacarpals, second toe duplication and preaxial polydactyly on the right hand. These features have been never reported before in patients with pathogenic FAT1 variants and support the role of this gene in the development of limb buds. Notably, each parent was heterozygous for both of these variants, which were ultra-rare and rare, respectively. This study raises awareness about the value of using whole exome/genome sequencing rather than targeted gene panels when testing affected offspring born to consanguineous couples. In this way, exomic data from the parents are also made available for carrier screening, to identify heterozygous pathogenetic and likely pathogenetic variants in genes responsible for other recessive conditions, which may pose a risk for subsequent pregnancies.

SUBMITTER: Peluso F

PROVIDER: S-EPMC8303193 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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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Whole Exome Sequencing Is the Minimal Technological Approach in Probands Born to Consanguineous Couples.

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