A reference for the consult room.

DLL1 (HGNC:2908; OMIM 606582) encodes Delta-like Canonical Notch Ligand 1, a 723-aa type-I transmembrane DSL-family ligand. Heterozygous loss-of-function causes NEDBAS (OMIM #618709; Fischer-Zirnsak et al., 2019). Biallelic missense variants — to date a single c.1534G>A (p.Gly512Arg) consanguineous family — cause SCDO7. Terminal 6q27 deletions remove DLL1 alongside neighbours and produce a spectrum scaling with deletion size. See Understanding DLL1 for the full picture.

Reported NEDBAS variants span nonsense, frameshift, canonical splice, missense, and whole-gene deletions, consistent with haploinsufficiency. Apply ACMG/AMP criteria with attention to PVS1 (LoF in a haploinsufficient gene), PM2_supporting (gnomAD absence), PS2/PM6 (de novo), and PP1 (segregation). Many missense variants remain VUS pending functional or segregation data — flag for re-evaluation rather than ruling out.

NEDBAS: developmental delay / ID (~86%), brain MRI abnormalities (~73%), facial dysmorphism (~53%), ASD / seizures / hypotonia (~43% each), scoliosis (~27%). SCDO7: severe vertebral fusion (T4–T5, T6–T8, T11–T12), progressive scoliosis, rib segmentation defects. 6q27 deletions: reduced cerebellar diameter, ventriculomegaly (often prenatal), multi-system findings depending on co-deleted loci.

First-line: trio whole exome sequencing — DLL1 has conventional exonic structure and is reliably called by WES. WGS adds structural variants and 6q27 deletions in one assay. CMA is required to characterise deletion breakpoints. Confirm DLL1 is included on any ID/epilepsy panel before relying on it.

Consider Alagille syndrome (JAG1), Adams-Oliver syndrome (DLL4 / NOTCH1), CADASIL (NOTCH3), and SCDO1 (DLL3) for overlapping Notch-pathway phenotypes. The DLL1 fingerprint is the combination of variable neurodevelopmental features with subtle skeletal findings — distinct from the cholestatic / cardiac / vascular emphases of its Notch siblings.

There is no DLL1-specific therapy. Care is symptom-directed: developmental and educational supports, anti-seizure medication when indicated, spine surveillance (especially if vertebral findings are present), and routine paediatric care. Multidisciplinary input — neurology, genetics, developmental paediatrics, orthopaedics — is the norm.

Heterozygous LoF behaves dominantly with variable expressivity; recurrence risk is 50% from an affected parent and ~1% (germline mosaicism) for confirmed de novo cases. SCDO7 follows autosomal recessive inheritance with 25% recurrence and carrier testing for at-risk relatives. 6q27 deletions are usually de novo but parental karyotype / FISH should be considered.

If you are evaluating a patient with a DLL1 variant or a 6q27 deletion, please reach out. Every additional well-phenotyped case sharpens variant interpretation for the next family.