| Title: |
Long‐Read Whole‐Genome Sequencing Uncovers a Deletion Upstream to HOXD13 Causing Synpolydactyly |
| Authors: |
Rips, Jonathan; Birnbaum, Rivka; Jalas, Chaim; Frumkin, Ayala; Zenvirt, Shamir; Rachanaev, Julia; Shaag, Avraham; Harel, Tamar; Elpeleg, Orly; Mor‐Shaked, Hagar |
| Source: |
American Journal of Medical Genetics Part A ; volume 197, issue 10 ; ISSN 1552-4825 1552-4833 |
| Publisher Information: |
Wiley |
| Publication Year: |
2025 |
| Collection: |
Wiley Online Library (Open Access Articles via Crossref) |
| Description: |
Synpolydactyly (SPD) is a heterogeneous distal‐limb malformation syndrome, characterized by webbing and duplication of adjacent digits. SPD1, the most common type, is attributed to disease‐causing variants in HOXD13, a transcription factor in the HOXD cluster that is essential for limb development. Here, we present a challenging exome‐negative case of familial SPD. The case was resolved using long‐read genome sequencing, which revealed a microdeletion in a conserved noncoding regulatory region upstream of the HOXD cluster. Oxford Nanopore WGS‐LRS was pursued on two affected sisters, followed by CMA‐Cytoscan HT validation. WGS‐LRS for two affected siblings revealed a shared microdeletion of ~5.6 kb upstream of EVX2 and HOXD13 [chr2:176073523–176,079,120 (hg38)]. The deletion is predicted to affect the enhancer of several HOXD genes (EH38E2053988) and overlaps with a short stretch of high‐sequence homology between human and mouse, called R1. CMA‐Cytoscan HT analysis and PCR validation approved segregation of the deletion in the siblings and revealed a paternal inheritance. Our findings expand the genotype–phenotype correlation of the regulatory region upstream of HOXD13 in SPD and highlight the utility of long‐read WGS for detecting noncoding variants that are undetectable by exome sequencing. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1002/ajmg.a.64130 |
| Availability: |
https://doi.org/10.1002/ajmg.a.64130; https://onlinelibrary.wiley.com/doi/pdf/10.1002/ajmg.a.64130 |
| Rights: |
http://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.AC913063 |
| Database: |
BASE |