Abstract
Background: The SHH gene (MIM *600725) encodes a protein that is involved in establishing
cell fates at several points during embryogenesis.
In this case report, we describe two children with a variant of uncertain significance in the SHH gene.
Methods: Individuals were examined at Medical Genetics and Prenatal diagnostics department of Latvian Children’s Clinical University Hospital. Written consent was obtained from all participants.
Results: The clinical geneticist consulted the first child due to holoprosencephaly. DNA testing revealed variant of unknown significance (VUS) c.427G>C,p.(Gly143Arg) in the SHH gene. Child died before the age of one year. Variant segregation revealed that the probands’ father is the carrier of the variant. Phenotyping of both parents was made – father had hypotelorism, epicanthal folds and cleft palate. Prenatal consult was done for family, but further testing was not offered. The second child was born with unilateral choanal atresia, currently progressive microcephaly, and developmental delay. Second child underwent clinical-exome sequencing, which revealed the same variant in the SHH gene.
Conclusion: The variant was not previously described and was absent from gnomAD. It is localized in the hotspot of missense variants, and pathogenic variant is described in the same codon. From clinical point of view, variant should be classified as likely pathogenic. Pathogenic variants in SHH gene have variable expressivity. This poses a challenge in prenatal diagnosis, even more when the variant classification is not straightforward.
Findings of this case report highlight the importance of SHH variants evaluation and developing a better understanding of the genotype-phenotype correlation.
cell fates at several points during embryogenesis.
In this case report, we describe two children with a variant of uncertain significance in the SHH gene.
Methods: Individuals were examined at Medical Genetics and Prenatal diagnostics department of Latvian Children’s Clinical University Hospital. Written consent was obtained from all participants.
Results: The clinical geneticist consulted the first child due to holoprosencephaly. DNA testing revealed variant of unknown significance (VUS) c.427G>C,p.(Gly143Arg) in the SHH gene. Child died before the age of one year. Variant segregation revealed that the probands’ father is the carrier of the variant. Phenotyping of both parents was made – father had hypotelorism, epicanthal folds and cleft palate. Prenatal consult was done for family, but further testing was not offered. The second child was born with unilateral choanal atresia, currently progressive microcephaly, and developmental delay. Second child underwent clinical-exome sequencing, which revealed the same variant in the SHH gene.
Conclusion: The variant was not previously described and was absent from gnomAD. It is localized in the hotspot of missense variants, and pathogenic variant is described in the same codon. From clinical point of view, variant should be classified as likely pathogenic. Pathogenic variants in SHH gene have variable expressivity. This poses a challenge in prenatal diagnosis, even more when the variant classification is not straightforward.
Findings of this case report highlight the importance of SHH variants evaluation and developing a better understanding of the genotype-phenotype correlation.
| Original language | English |
|---|---|
| Pages | 230 - 230 |
| Number of pages | 1 |
| Publication status | Published - 2023 |
| Externally published | Yes |
| Event | European Human Genetics Conference - Hybrid Conference, Glasgow, United Kingdom Duration: 10 Jun 2023 → 13 Jun 2023 https://2023.eshg.org/ https://2023.eshg.org |
Conference
| Conference | European Human Genetics Conference |
|---|---|
| Abbreviated title | ESHG |
| Country/Territory | United Kingdom |
| City | Glasgow |
| Period | 10/06/23 → 13/06/23 |
| Internet address |
Field of Science*
- 3.1 Basic medicine
Publication Type*
- 3.4. Other publications in conference proceedings (including local)