Dataset Information

Routine Diagnostics Confirm Novel Neurodevelopmental Disorders.

ABSTRACT: Routine diagnostics is biased towards genes and variants with satisfactory evidence, but rare disorders with only little confirmation of their pathogenicity might be missed. Many of these genes can, however, be considered relevant, although they may have less evidence because they lack OMIM entries or comprise only a small number of publicly available variants from one or a few studies. Here, we present 89 individuals harbouring variants in 77 genes for which only a small amount of public evidence on their clinical significance is available but which we still found to be relevant enough to be reported in routine diagnostics. For 21 genes, we present case reports that confirm the lack or provisionality of OMIM associations (ATP6V0A1, CNTN2, GABRD, NCKAP1, RHEB, TCF7L2), broaden the phenotypic spectrum (CC2D1A, KCTD17, YAP1) or substantially strengthen the confirmation of genes with limited evidence in the medical literature (ADARB1, AP2M1, BCKDK, BCORL1, CARS2, FBXO38, GABRB1, KAT8, PRKD1, RAB11B, RUSC2, ZNF142). Routine diagnostics can provide valuable information on disease associations and support for genes without requiring tremendous research efforts. Thus, our results validate and delineate gene-disorder associations with the aim of motivating clinicians and scientists in diagnostic departments to provide additional evidence via publicly available databases or by publishing short case reports.

SUBMITTER: Jauss RT

PROVIDER: S-EPMC9778535 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Routine Diagnostics Confirm Novel Neurodevelopmental Disorders.

Jauss Robin-Tobias RT Schließke Sophia S Abou Jamra Rami R

Genes 20221207 12

Routine diagnostics is biased towards genes and variants with satisfactory evidence, but rare disorders with only little confirmation of their pathogenicity might be missed. Many of these genes can, however, be considered relevant, although they may have less evidence because they lack OMIM entries or comprise only a small number of publicly available variants from one or a few studies. Here, we present 89 individuals harbouring variants in 77 genes for which only a small amount of public eviden ...[more]

PMID: 36553572

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Project description:Infertility is a common condition estimated to affect 10-15% of couples. The clinical causes are attributed in equal parts to the male and female partners. Diagnosing male infertility mostly relies on semen (and hormone) analysis, which results in classification into the two major phenotypes of oligo- and azoospermia. The clinical routine analyses have not changed over the last 20 years and comprise screening for chromosomal aberrations and Y‑chromosomal azoospermia factor deletions. These tests establish a causal genetic diagnosis in about 4% of unselected men in infertile couples and 20% of azoospermic men. Gene sequencing is currently only performed in very rare cases of hypogonadotropic hypogonadism and the CFTR gene is routinely analysed in men with obstructive azoospermia. Still, a large number of genes have been proposed to be associated with male infertility by, for example, knock-out mouse models. In particular, those that are exclusively expressed in the testes are potential candidates for further analyses. However, the genome-wide analyses (a few array-CGH, six GWAS, and some small exome sequencing studies) performed so far have not lead to improved clinical diagnostic testing. In 2017, we started to routinely analyse the three validated male infertility genes: NR5A1, DMRT1, and TEX11. Preliminary analyses demonstrated highly likely pathogenic mutations in these genes as a cause of azoospermia in 4 men, equalling 5% of the 80 patients analysed so far, and increasing the diagnostic yield in this group to 25%. Over the past few years, we have observed a steep increase in publications on novel candidate genes for male infertility, especially in men with azoospermia. In addition, concerted efforts to achieve progress in elucidating genetic causes of male infertility and to introduce novel testing strategies into clinical routine have been made recently. Thus, we are confident that major breakthroughs concerning the genetics of male infertility will be achieved in the near future and will translate into clinical routine to improve patient/couple care.

Dataset Information

Routine Diagnostics Confirm Novel Neurodevelopmental Disorders.

Publications

Routine Diagnostics Confirm Novel Neurodevelopmental Disorders.

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