Table 1.
Findings Pertaining to Monogenic-Disease Risk
| Phenotype at Enrollment | Sex | Ethnicity or Race | Gene (Transcript) | Variant(s), (Classification) | Zygosity | Disease | Inh | Parent of Origin | Penetrancea |
|---|---|---|---|---|---|---|---|---|---|
| Well-Baby Cohort | |||||||||
| healthy | m | white | BRCA2b (GenBank: NM_000059.3) | c.8297delC (p.Thr2766Asnfs∗11), (P) | het | hereditary breast and ovarian cancer | AD | mat | high |
| healthy | f | white | BTD (GenBank: NM_000060.2) | c.[44+1G>A;1612C>T] (p.[?;Arg538Cys]), (LP;P) | comp het | biotinidase deficiency | AR | mat & pat | high |
| healthy | f | unspecified | CD46 (GenBank: NM_002389.4) | c.286+2T>G (p.?), (LP) | het | atypical hemolytic-uremic syndrome | AD | mat | moderate |
| healthy | m | white | ELN (GenBank: NM_000501.3) | c.1957G>T (p.Gly653∗), (P) | het | supravalvular aortic stenosis | AD | pat | moderate |
| healthy | f | unspecified | KCNQ4 (GenBank: NM_004700.3) | c.1671_1672insACGAC (p.Val558Thrfs∗3), (LP) | het | non-syndromic hearing loss | AD | pat | high |
| healthy | m | white | MYBPC3 (GenBank: NM_000256.3) | c.1624G>C (p.Glu542Gln), (P) | het | hypertrophic cardiomyopathy | AD | mat | moderate |
| healthy | m | white | TTN (GenBank: NM_133378.4) | c.34894_34895insG (p.Met11632Serfs∗8), (LP) | het | dilated cardiomyopathy | AD | mat | moderate |
| healthy | f | multi-racial | TTN (GenBank: NM_133432.3) | c.12344delC (p.Pro4115Glnfs∗14), (LP) | het | dilated cardiomyopathy | AD | mat | moderate |
| healthy | m | unspecified | TTN (GenBank: NM_133378.4) | c.54172C>T (p.Arg18058∗), (LP) | het | dilated cardiomyopathy | AD | pat | moderate |
| healthy | f | white | TTN (GenBank: NM_133378.4) | c.64276_64282delinsTA (p.Ala21426∗), (P) | het | dilated cardiomyopathy | AD | pat | moderate |
| healthy | f | white | VCL (GenBank: NM_014000.2) | c.1713delA (p.Ala573Hisfs∗8), (LP) | het | dilated cardiomyopathy | AD | mat | moderate |
| NICU Cohort | |||||||||
| anteriorly displaced and imperforate anus | f | white | ANKRD11 (GenBank: NM_001256182.1) | c.2409_2412del (p.Glu805Argfs∗57), (LP) | het | KBG syndrome | AD | de novo | high |
| hypoplastic left heart | m | white | BRCA2b (GenBank: NM_000059.3) | c.3545_3546del (p.Phe1182∗), (P) | het | hereditary breast and ovarian cancer | AD | mat | high |
| congenital severe chronic lung disease | f | unspecified | CYP21A2 (GenBank: NM_000500.7) | c.[844G>T;1447C>T] (p.[Val282Leu;Pro483Ser]), (P;P) | comp hetc | congenital adrenal hyperplasia due to 21-hydroxylase deficiency | AR | unkc & pat | high |
| aortic coarctation | m | native Hawaiian or other Pacific Islander | G6PD (GenBank: NM_000402.3) | c.961G>A (p.Val321Met), (LP) | hem | glucose-6-phosphate dehydrogenase deficiency | XLR | mat | moderate |
| tetralogy of Fallot, pulmonic stenosis, and cryptorchidism | m | white | GLMN (GenBank: NM_053274.2) | c.554_558delinsG (p.Lys185Serfs∗19), (LP) | het | glomuvenous malformations | AD | pat | high |
| respiratory distress (surfactant deficiency) and hypoglycemia | f | multi-racial | MSH2b (GenBank: NM_000251.2) | c.1637_1638insA (p.Asn547Glufs∗4), (P) | het | Lynch syndrome | AD | mat | high |
| neonatal pneumonia and meconium aspiration | m | white | SLC7A9 (GenBank: NM_014270.4) | c.614dupA (p.Asn206Glufs∗3), (P) | het | cystinuria | AD | mat | moderate |
Abbreviations are as follows: m = male; f = female; AD = autosomal-dominant; AR = autosomal-recessive; XLR = X-linked recessive; P = pathogenic; LP = likely pathogenic; het = heterozygous; hom = homozygous; hem = hemizygous; comp het = compound-heterozygous; mat = maternal; and pat = paternal, unk = unknown.
Estimated penetrance for the gene was defined on the basis of curated literature for reported individuals with pathogenic variants in the gene. It was classified as “high” if ≥80% of individuals were symptomatic, “moderate” if 20%–80% of individuals were symptomatic, and “low” if <20% of individuals were symptomatic, as described.6
Actionable adult-onset finding; please see text for explanation.
Although the p.Pro483Ser variant was confirmed to be paternally inherited, the p.Val282Leu variant could not be confirmed in either parent via standard Sanger sequencing. On the basis of multiple occurences in the literature of the two variants on separate chromosomes, these variants were reported to confer disease risk in the newborn in this study. The need to confirm their phase in the newborn by parental testing using targeted CYP21A2 long-range PCR assay was explained in the newborn’s nGS report.