DLL1-Related Diseases via the DLL1 Gene

Neurodevelopmental disorder with nonspecific brain abnormalities, with or without seizures, is a phenotypically variable genetic condition caused by pathogenic single nucleotide or copy number variant changes in the delta like canonical Notch ligand 1 (DLL1) gene. To date, 14 individuals from 11 unrelated families have been identified with DLL1 gene disrupting single nucleotide variants (Fischer-Zirnsak et al. 2019. PubMed ID: 31353024). The most common clinical features in this cohort were intellectual disability (86%), variable brain malformations (79%), autism spectrum disorder (43%), seizures (43%), hypotonia (40%), and scoliosis (27%). Brain abnormalities observed are non-specific and include hydrocephalus, ventriculomegaly, anomalies of the corpus callosum, cortical dysplasia, a small cerebellum/pons, and periventricular nodular heterotopias (Fischer-Zirnsak et al. 2019. PubMed ID: 31353024). The age of diagnosis is variable, spanning from birth to adulthood, with 40% of cases found to have abnormal prenatal brain imaging.

Changes in the DLL1 gene have also been associated with holoprosencephaly (HPE). Holoprosencephaly is the most common congenital malformation of the developing human brain. It is characterized by defective division of the forebrain into distinct left and right hemispheres. The clinical spectrum of HPE includes a broad range of craniofacial anomalies or malformations (Tekendo-Ngongang et al. 2020. PMID: 20301702). Clinical manifestations commonly observed in children with HPE include developmental delays, seizures, hydrocephalus, neural tube defects, hypothalamic and brain stem dysfunction, pituitary dysfunction, short stature, failure to thrive, and feeding difficulties. Erratic sleep patterns can be observed (Tekendo-Ngongang et al. 2000. PMID: 20301702). The etiology of HPE is highly heterogeneous and complex, involving numerous genetic and environmental factors. Approximately 25%-50% of individuals diagnosed with HPE have a numerical or structural chromosomal abnormality or a pathogenic copy number variant. In addition, pathogenic variants in single genes account for approximately 18-25% of syndromic holoprosencephaly. Nonsyndromic or isolated HPE is most associated with genetic changes in SHH, ZIC2, SIX3, and TGIF1. Other less commonly monogenetic causes such as DLL1 variants are observed in fewer than 1% of all cases diagnosed with nonsyndromic HPE (Tekendo-Ngongang et al. 2020. PMID: 20301702).

Currently, there are no treatments for conditions caused by variants in DLL1. However, genetic testing may provide several advantages, including differential diagnosis and prognostic information to predict the expected severity and course of the disorder. Early identification and treatment of symptoms such as seizures and scoliosis; prenatal testing or pre-implantation genetic diagnosis for future pregnancies; and facilitating access to therapeutic, social, and educational services and benefits may also be possible as a result of genetic testing.

Neurodevelopmental disorder with nonspecific brain abnormalities, with or without seizures is an autosomal dominant condition. De novo and dominantly inherited heterozygous DLL1 pathogenic variants (nonsense, missense, splice site, and gene deletion) are reported as the cause of developmental delays, intellectual disability, ASD, seizures, variable brain malformations, and scoliosis (Fischer-Zirnsak et al. 2019. PubMed ID: 31353024).

DLL1 resides in the 6q27 chromosome region. Significant phenotypic overlap among the above-mentioned cases and individuals positive for 6q27 microdeletions which are highly suspected to be associated with DLL1 gene haploinsufficiency, has been observed. (Fischer-Zirnsak et al. 2019. PubMed ID: 31353024, Dupé et al. 2011. PubMed ID: 21196490, Conti et al. 2013. PubMed ID: 24056535, Peddibhotla. 2015. PubMed ID: 24736736). Several reports of monosomy for the terminal portion of the chromosome 6q, either due to the inheritance of unbalanced translocations or isolated de novo deletions have been described to date. It has been suggested that DLL1 may be key to the brain malformation phenotypes observed (Conti et al. 2013, PubMed ID: 24056535, Peddibhotla. 2015. PubMed ID: 24736736, Hanna et al. 2019, PMID 31602192). No clear genotype-phenotype correlation has emerged from these studies; however, the smallest region of overlap possibly associated with the phenotype of brain malformations and intellectual disability maps to a segment of 325 kb, comprising the DLL1, PSMB1, TBP, and PDCD2 genes (Hanna et al. 2019. PMID: 31602192). DLL1 is relatively intolerant to loss of function variants (Genome Aggregation Database). Overall, DLL1 has been cited as a nonessential gene for growth of human tissue culture cells (Online Gene Essentiality).

DLL1 is an important ligand for the Notch3 receptor and activation of Notch3 signaling cascade (Steinbuck et al. 2018. PMID: 29910816). This signaling pathway is evolutionarily conserved and plays a critical role in neural proliferation, migration, and differentiation during embryonic development of the nervous system (Lasky et al. 2005. PMID: 15817497). Four other Notch ligands have been associated with human monogenic diseases: monoallelic pathogenic variants in JAG1 causing Alagille syndrome 1 and tetralogy of Fallot, monoallelic pathogenic variants in JAG2 causing autosomal recessive limb-girdle muscular dystrophy-27 (LGMDR27), monoallelic pathogenic variants in DLL4 causing Adams-Olliver syndrome 6, and biallelic pathogenic variants in DLL3 causing spondylocostal dysostosis 1.

Neurodevelopmental disorder with nonspecific brain abnormalities, with or without seizures, is very rare, with fewer than 100 patients reported worldwide. Therefore, it is difficult to estimate the clinical sensitivity of this test. Approximately 1.2% of cases from a cohort of 257 individuals diagnosed with HPE  harbored pathogenic variants in DLL1 gene (Dubourg et al. 2016. PubMed ID: 27363716).

Analytical sensitivity of this test is expected to be very high (>98%), as the test method will detect the vast majority of known pathogenic variants in DLL1, including copy number variants (CNVs).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the DLL1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).