Feingold Syndrome 1 via the MYCN Gene

Feingold syndrome 1 (FS1), also known as oculo-digito-esophageal-duodenal syndrome or ODED syndrome, is a rare congenital disorder typically characterized by brachymesophalangy (short middle phalanx of finger), toe syndactyly, microcephaly, short palpebral fissures, mild learning deficits, and short stature (less than tenth percentile). Minor features of FS1 include thumb hypoplasia, micrognathia, renal abnormalities, cardiac abnormalities and hearing loss. Some patients have also demonstrated atresia of the esophagus, duodenum, jejunum, and/or anus (Celli et al. 2003. PubMed ID: 14518066). Currently, the incidence of FS1 is unknown as reports are limited to case reports and small familial studies, but is estimated to be very rare (less than 1 in 1,000,000). The genetic cause of FS1 was mapped to chromosome 2p23-24 (Celli et al. 2003. PubMed ID: 14518066), and eventually MYCN was identified as the causative gene (van Bokhoven et al. 2005. PubMed ID: 15821734).

Genetic testing for FS1 through MYCN analysis can be used to molecularly confirm a clinical diagnosis, inform reproductive decision making in families with known or suspected cases of FS1, and identify de novo variants in known or suspected FS1 cases.

FS1 is inherited in an autosomal dominant manner through pathogenic variants in MYCN. FS1 appears to have complete penetrance with variable expressivity, even within families (Blaumeiser et al. 2008. PubMed ID: 18671284). A very similar disorder with the same phenotype presentation with the exception of gastrointestinal anomalies, known as Feingold syndrome 2, is caused by pathogenic variants in MIR17HG.

Reported pathogenic variants in MYCN include missense, nonsense, small frameshift deletions, small framshift insertions/duplications, and gross deletions. The majority of affected individuals have small pathogenic variants within the MYCN sequence, and there are no significant differences in clinical presentation reported amongst these individuals. Large deletions of chromosome 2p, including MYCN as well as surrounding genes, typically present as FS1 with additional clinical features (Burnside et al. 2018. PubMed ID: 30088856).

The MYCN protein is a nuclear transcription factor implicated in developmental processes. Thus, variants in the helix-loop-helix (HLH) domain, which is crucial for DNA binding, and nonsense variants that occur upstream of the HLH domain, are often found to be pathogenic (Blaumeiser et al. 2008. PubMed ID: 18671284; van Bokhoven et al. 2005. PubMed ID: 15821734). The majority of pathogenic variants reported in MYCN are present in exon 3, but a small proportion of variants have also been reported in exon 2 (Blaumeiser et al. 2008. PubMed ID: 18671284; Cognet et al. 2011. PubMed ID: 21224895; Marcelis et al. 2008. PubMed ID: 18470948).

Although the bulk of reported FS1 cases with MYCN variants are familial, de novo variants have also been reported (Blaumeiser et al. 2008. PubMed ID: 18671284; Cognet et al. 2011. PubMed ID: 21224895; Marcelis et al. 2008. PubMed ID: 18470948; Yu et al. 2018. PubMed ID: 29786759).

Several mouse models for FS1 and MYCN loss have been created. Conditional knockout of Mycn in myocardial tissue results in thin myocardial walls (Harmelink et al. 2013. PubMed ID: 23063798) and conditional knockout of Mycn in developing limbs results in severe brachysyndactyly (Mirzamohammadi et al. 2018. PubMed ID: 29636449), similar to that observed in FS1 patients. Homozygous deletion of Mycn results in embryonic lethality approximately half way through mouse gestation (Charron et al. 1992. PubMed ID: 1459450).

This test has an estimated clinical sensitivity of 68% for detecting Feingold syndrome 1 in patients that display clinical features associated with FS1 (Blaumeiser et al. 2008. PubMed ID: 18671284; Cognet et al. 2011. PubMed ID: 21224895; Marcelis et al. 2008. PubMed ID: 18470948; van Bokhoven et al. 2005. PubMed ID: 15821734). The remaining individuals frequently are diagnosed with syndromes with significant phenotypic overlap, including Feingold syndrome 2, CHARGE syndrome, Fanconi Anemia, and VACTERL association (Marcelis et al. 2019. PubMed ID: 20301770).

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 MYCN gene plus 10 bases flanking noncoding DNA in all available transcripts in addition to 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).