Rare Genetic Mechanisms in Dyggve-Melchior-Clausen Disease
Abstract
Dyggve-Melchior-Clausen disease (DMC) is a rare skeletal dysplasia caused by biallelic variants in DYM. We investigated four affected individuals from three families with classical DMC features and non-diagnostic whole-exome sequencing. Reanalysis identified a homozygous deep intronic variant, DYM: c.193+132G>T, in Family 1 and a homozygous 331-bp AluYb8 insertion in exon 12 in Family 2. CRISPR prime editing and transcript analysis demonstrated that c.193+132G>T activates cryptic splice sites, resulting in 13-bp and 67-bp pseudoexon inclusion predicted to disrupt the reading frame. A missense variant of uncertain significance was identified in Family 3. These findings expand the mutational spectrum of DYM and highlight the value of investigating non-coding and structural variants in patients with a strong DMC phenotype.
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BibTeX
@misc{jacob2026rare,
title = {{Rare Genetic Mechanisms in Dyggve-Melchior-Clausen Disease}},
author = {Prince Jacob and Lingjuan Hong and Deepa Bhat and KN Gopika and Shushu Huang and Benjamin Kramer and K Mohandas Nair and Monkol Lek and Siddaramappa J Patil},
howpublished = {medRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.22.26365648},
url = {https://www.medrxiv.org/content/10.64898/2026.10.22.26365648v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Rare Genetic Mechanisms in Dyggve-Melchior-Clausen Disease
AU - Prince Jacob
AU - Lingjuan Hong
AU - Deepa Bhat
AU - KN Gopika
AU - Shushu Huang
AU - Benjamin Kramer
AU - K Mohandas Nair
AU - Monkol Lek
AU - Siddaramappa J Patil
PY - 2026
DA - 2026/10/22
PB - medRxiv
DO - 10.64898/2026.10.22.26365648
UR - https://www.medrxiv.org/content/10.64898/2026.10.22.26365648v1
AB - Dyggve-Melchior-Clausen disease (DMC) is a rare skeletal dysplasia caused by biallelic variants in DYM. We investigated four affected individuals from three families with classical DMC features and non-diagnostic whole-exome sequencing. Reanalysis identified a homozygous deep intronic variant, DYM: c.193+132G>T, in Family 1 and a homozygous 331-bp AluYb8 insertion in exon 12 in Family 2. CRISPR prime editing and transcript analysis demonstrated that c.193+132G>T activates cryptic splice sites, resulting in 13-bp and 67-bp pseudoexon inclusion predicted to disrupt the reading frame. A missense variant of uncertain significance was identified in Family 3. These findings expand the mutational spectrum of DYM and highlight the value of investigating non-coding and structural variants in patients with a strong DMC phenotype.
ER -