Adams-Oliver Syndrome Panel

Adams-Oliver syndrome (AOS) is a congenital condition characterized mainly by aplasia cutis congenita and limb defects with an estimated incidence of 1 in 225,000 live births (Saeidi and Ehsanipoor. 2017. PubMed ID: 29387678). The clinical features include congenital missing skin typically on the top of the skull, tapering fingers, and hyperplastic distal phalanges of the hands and feet. Some patients may have heart problems, including ventricular septal defect and patent ductus arteriosus (Shaheen et al. 2013. PubMed ID: 23522784; Hassed et al. 2012. PubMed ID: 22883147; Lehman et al. 2016. PubMed ID: 27077170; Meester et al. 2018. PubMed ID: 29924900). Pathogenic variants in KCTD1 are associated with Scalp-Ear-Nipple (SEN) syndrome, which is characterized by cutis aplasia of the scalp; minor defects of the external ears, digits, and nails; and malformed breast (Marneros et al. 2013. PubMed ID: 23541344). Molecular genetic testing is advantageous to establish an accurate diagnosis for individuals with Adams-Oliver syndrome or related conditions.

Pathogenic variants in ARHGAP31, DLL4, NOTCH1, RBPJ, and MYH9 cause autosomal dominant AOS, while pathogenic variants in DOCK6 and EOGT cause autosomal recessive Adams-Oliver syndrome (Shaheen et al. 2013. PubMed ID: 23522784; Hassed et al. 2012. PubMed ID: 22883147; Isrie et al. 2014. PubMed ID: 24668619; Uyeda et al. 2012. PubMed ID: 22631568; Lehman et al. 2016. PubMed ID: 27077170). This panel includes genes known to cause Adams-Oliver syndrome, as well as KCTD1, which is involved in autosomal dominant scalp-ear-nipple syndrome (Marneros et al. 2013. PubMed ID: 23541344). 

The DOCK6 and ARHGAP31 proteins are GTPase-accelerating proteins (GAP) and serve as switches between inactive GDP-bound and active GTP-bound, particularly during development of the limbs, skull, and heart (Southgate et al. 2011. PubMed ID: 21565291). The DLL4, NOTCH1, RBPJ, and EOGT proteins are involved in the NOTCH signal pathway which regulates cell-fate determination during development and maintains adult tissue homeostasis (Hori et al. 2013. PubMed ID: 23729744). The types of pathogenic variants reported include missense, nonsense, splicing, small deletion/insertion, large deletion/insertion, regulatory and complex rearrangment (Human Gene Mutation Database).

In the following table are the shown the fraction of AOS cases that are explained by pathogenic variants in the indicated genes.

Table from Lehman et al. 2016.

At least one de novo MYH9 pathogenic variant was reported in one patient with congenital scalp hemangioma (Fomchenko. 2018. PubMed ID: 29903892).

See individual gene summaries for more information about molecular biology of gene products and spectra of pathogenic variants.

Pathogenic variants were found in 36%-50% of Adams-Oliver syndrome cases (Lehman et al. 2016. PubMed ID: 27077170; Meester et al. 2018. PubMed ID: 29924900). Large deletions or duplications were reported in NOTCH1, RBPJ, and DOCK6 (Westphal. 2019. PubMed ID: 30868567; Liang et al. 2016. PubMed ID: 28030855; Sukalo et al. 2015. PubMed ID: 25824905; Human Gene Mutation Database).

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

This panel provides 100% coverage of all coding exons of the genes 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 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).