DYNC2H1 splicing variants causing severe prenatal short-rib polydactyly syndrome and postnatal orofaciodigital syndrome.
DYNC2H1
RNA splice sites
ciliopathies
genetic testing
orofaciodigital syndromes
short‐rib polydactyly syndrome
Journal
Annals of human genetics
ISSN: 1469-1809
Titre abrégé: Ann Hum Genet
Pays: England
ID NLM: 0416661
Informations de publication
Date de publication:
03 Oct 2024
03 Oct 2024
Historique:
revised:
16
09
2024
received:
11
05
2024
accepted:
17
09
2024
medline:
3
10
2024
pubmed:
3
10
2024
entrez:
3
10
2024
Statut:
aheadofprint
Résumé
The DYNC2H1 gene has been associated with short-rib polydactyly syndrome (SRPS), among other skeletal ciliopathies. Two cases are presented of distinctive phenotypes resulting from splicing variants in DYNC2H1. The first is a 14-week-old fetus with enlarged nuchal translucency, oral hamartoma, malformed uvula, bifid epiglottis, short ribs, micromelia, long bone agenesis, polysyndactyly, heart defect, pancreatic cysts, multicystic dysplastic kidney, megabladder and trident acetabulum. A ciliopathies NGS panel revealed two compound heterozygous variants in DYNC2H1: c.7840-18T>G r.7841_7964del p.Gly2614Aspfs*5 and c.11070G>A r.11044_11116del p.Ile3682Aspfs*2. Both variants were initially classified as variants of uncertain significance but were reclassified as likely pathogenic after PCR-based RNA testing. The second is an 11-year-old overweight male with multiple accessory oral frenula, median cleft lip and alveolar ridge, polysyndactyly, brachydactyly, normal rib length, and hypogonadism. Exome sequencing revealed two compound heterozygous variants in DYNC2H1: c.6315del p.(Thr2106Glnfs*7), classified as likely pathogenic, and c.3303-16A>G p.(?), classified as a variant of uncertain significance. PCR-based RNA testing suggested that c.3303-16A>G induces an in-frame deletion: r.3303_3458del p.Asp1102_Arg1153del, although the normal transcript is still produced. These results are consistent with both SRPS type I/III in the first case and orofaciodigital syndrome in the second, an unprecedented description. This work thus improves the clinical and molecular knowledge of the phenotypes associated with splicing variants in the DYNC2H1 gene.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2024 University College London (UCL) and John Wiley & Sons Ltd.
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