Table 2. Logistic Regression Model Score of 15 Possibly Diagnostic Variants of Unknown Significance.
| ID No. | Sex assigned at birth | Primary category inclusion criteriaa | Secondary category inclusion criteria, HPO terms | HPO terms submitted in analysis pipeline | Gene | NM_number | Variant | Phase | Syndrome or disorder | MIM No. | Inheritance | Probabilityb | Model scoreb |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | Female | 2 | HP:0001627, HP:0000924, HP:0000818 | Abnormal heart morphology, HP:0001627; femoral bowing, HP:0002980; tibial bowing, HP:0002982; talipes equinovarus, HP:0001762; kyphoscoliosis, HP:0002751; respiratory distress, HP:0002098; abnormal facial shape, HP:0001999; macrocephaly, HP:0000256; ventricular septal defect, HP:0001629; cryptorchidism, HP:0000028; rocker bottom foot, HP:0001838 | PHEX | NM_000444.6 | c.751A>G, p.Lys251Glu | Heterozygote | Hypophosphatemic rickets | 307800 | XLD, maternal | 0.644 | 1 |
| 2 | Male | 2 | HP:0001197 | Bifid scrotum, HP:0000048; cleft lip, HP:0410030; cleft palate, HP:0000175 | GLI3 | NM_000168.6 | c.613C>T, p.Arg205Cys | Heterozygote | Pallister Hall syndrome vs Greig cephalopolysyndactyly syndrome | 146510 vs 175700 | Paternal | 0.784 | 1 |
| ARHGAP29 | NM_004815.4 | c.2127_2128dupTG, p.Gly710fs | Heterozygote | Cleft lip with or without cleft palate | MONDO:0016034, ORPHA:199306 | De novo | |||||||
| 3 | Male | 5 | HP:0001627, HP:0000818 | Abnormal prolactin level, HP:0040086; abnormal pulmonary artery morphology, HP:0030966; hypertelorism, HP:0000316; brachyturricephaly, HP:0000244; atrial septal defect, HP:0001631; central hypothyroidism, HP:0011787; hyperinsulinemia, HP:0000842; wide nasal bridge, HP:0000431 | NA | NA | Chromosome 6:110 747 678-117 730 196 (approximately 6.983 Mb) dup | NA | Nonrecurrent copy number abnormality | NA | De novo | 0.294 | 0 |
| 4 | Female | 2 | HP:0001627, HP:0011024 | Situs inversus totalis, HP:0001696; biliary atresia, HP:0005912 | New candidate gene | NA | NA | Compound heterozygote | NA | NA | NA | 0.657 | 1 |
| 5 | Female | 2 | HP:0000951, HP:0011024 | Anal atresia, HP:0002023; preaxial hand polydactyly, HP:0001177; ventricular septal defect, HP:0001629; supernumerary ribs, HP:0005815 | GLI3 | NM_000168.5 | c.1984T>G p.Ser662Ala | Heterozygote | Pallister-Hall syndrome | 146510 | Maternal | 0.209 | 0 |
| 6 | Female | 3 | HP:0002086 | Ventilator dependence with inability to wean, HP:0005946; pulmonary arterial hypertension, HP:0002092; abnormal pulmonary interstitial morphology, HP:0006530; abnormal respiratory system physiology, HP:0002795 | SLC18A3 | NM_003055.3 | c.680T>C, p.Val227Ala | Homozygote | Myasthenic syndrome, congenital, 21, presynaptic | 617239 | AR | 0.233 | 0 |
| MYPN | NM_032578.3 | c.83G>C, p.Gly28Ala | Homozygote | Nemaline myopathy 11 | 617336 | AR | |||||||
| DMD | NM_004006.2 | c.3506T>C, p.Met1169Thr | Hemizygote | Becker muscular dystrophy | 300376 | XLR | |||||||
| 7 | Female | 5 | HP:0000818, HP:0001250 | Hypoglycemia, HP:0001943; hyperinsulinemic hypoglycemia, HP:0000825; convulsive status epilepticus, HP:0032660; congestive heart failure, HP:0001635; patent ductus arteriosus, HP:0001643; mitral regurgitation, HP:0001653; tricuspid regurgitation, HP:0005180; patent foramen ovale, HP:0001655; microcephaly, HP:0000252 | HNF4A | NM_001287184.1 | c.5C>T; p.Ser2Leu | Heterozygote | Fanconi renotubular syndrome 4, with maturity-onset diabetes of the young vs maturity-onset diabetes only | 616026 vs 125850 | Paternal | 0.559 | 1 |
| 8 | Male | 1 | HP:0001197, HP:0410263 | Hypoplasia of the corpus callosum, HP:0002079; abnormal facial shape, HP:0001999; postaxial polydactyly, HP:0100259; talipes calcaneovalgus, HP:0001884 | EVC2 | NM_147127.3 | c.1421T>C, p.Met474Thr | Homozygote | Ellis-van Creveld syndrome | 225500 | AR | 0.691 | 1 |
| ASH1L | NM_018489.1 | c.6929G>C; p.Gly2310Ala | Heterozygote | Intellectual developmental disorder, autosomal dominant 52 | 617796 | De novo | |||||||
| ADAMTSL1c | NM_001040272.6 | c.1414G>A, p.Gly472Arg | Homozygote | Microcephaly, facial dysmorphism, ocular anomalies, multiple congenital anomalies syndrome | ORPHA:521445 | Unknown | |||||||
| 9 | Male | 1 | HP:0001250, HP:0001298 | NA | CHD2 c | NM_001271.4 | c.295-125A>G | Heterozygote | Developmental and epileptic encephalopathy 94 | 615369 | De novo | 0.678 | 1 |
| CACNA1A | NM_001127222.2 | c.294-16973C>T | Heterozygote | Developmental and epileptic encephalopathy 42 | 617106 | De novo | |||||||
| 10 | Female | 5 | HP:0001939, HP:0011024, HP:0001290 | Thin upper lip vermilion, HP:0000219, chin with horizontal crease, HP:0011823, micrognathia, HP:0000347, jaundice, HP:0000952, conjugated hyperbilirubinemia, HP:0002908, infantile axial hypotonia, HP:0009062, cholestasis, HP:0001396, acholic stools, HP:0011985, long philtrum, HP:0000343, nasogastric tube feeding, HP:0040288 | GLIS3 c | NM_001042413.2 | c.2538G>A (p.Pro846Pro) maternal; c.1787C>T (p.Pro596Leu) paternal | Compound heterozygote | Neonatal diabetes with congenital hypothyroidism | 610199 | AR | 0.457 | 0 |
| 11 | Female | 1 | HP:0001250 | Dystonia, HP:0001332; feeding difficulties in infancy, HP:0008872; spasticity, HP:0001257; abnormal thalamic MRI signal intensity, HP:0012696; abnormal basal ganglia MRI signal intensity, HP:0012751 | RYR3 c | NM_001036.6 | c.1623C>A (p.Asn541Lys) maternal; c.9218G>A (p.Arg3073His) paternal | Compound heterozygote | Congenital myopathy 20 | 620310 | AR | 0.885 | 1 |
| 12 | Female | 1 | HP:0001250 | Myoclonic seizure, HP:0032794; abnormal isoelectric focusing of serum transferrin, HP:0003160 | GRIN1 | NM_007327.4 | c.1630C>T, p.Arg544Cys | Homozygote | Developmental and epileptic encephalopathy 101 | 619814 | AR | 0.889 | 1 |
| 13 | Female | 5 | HP:0000818 | Conjugated hyperbilirubinemia, HP:0002908, intrauterine growth retardation, HP:0001511, hyperinsulinemic hypoglycemia, HP:00008250, hypoglycemia, HP:0001943 | KCNJ11 | NM_000525.3 | c.635G>A, p.Ser212AsnS | Heterozygote | Hyperinsulinemic hypoglycemia, familial, 2 | 601820 | Maternal | 0.176 | 0 |
| GLUD1 | NM_005271.5 | c.1582T>A, p.Tyr528Asn | Heterozygote | Hyperinsulinism-hyperammonemia syndrome | 606762 | Paternal | |||||||
| IGFR1 | NM_000875.5 | c.1633G>A; p.Gly545Ser | Heterozygote | Insulin-like growth factor I, resistance to | 606762 | Paternal | |||||||
| 14 | Male | 2 | HP:0001197, HP:0000924, HP:0410263 | Bilateral cleft lip and palate, HP:0002744; foot oligodactyly, HP:0001849; agenesis of corpus callosum, HP:0001274 | FGFR1 c | NM_023110.3 | c.748C>G, p.Arg250Gly | Heterozygote | Holoprosencephaly, hypogonadotropic hypogonadism 2 with or without anosmia | 147950 | AD (paternal) | 0.942 | 1 |
| CHD6 | NM_032221.5 | c.176A>G, p.Lys59Arg | Heterozygote | Unknown | 616114 (gene) | AD (maternal) | |||||||
| 15 | Female | 2 | HP:0012210 | Pneumothorax, HP:0004876; polycystic kidney diseases, HP:0000113; macrosomia, HP:0001520 | FOXP3 c | NM_014009.4 | c.188C>T, p.Pro63Leu | Hemizygote | Immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome | 304790 | XLR (maternal) | 0.061 | 0 |
Abbreviations: AD, autosomal dominant; AR, autosomal recessive; HPO, human phenotype ontology; ID, identification; MIM, Mendelian Inheritance in Man; MRI, magnetic resonance imaging; NA, not applicable; XLD, X-linked dominant; XLR, X-linked recessive.
a
For primary category inclusion criteria see eTable 1 in Supplement 1.
b
For LR model (LR) see Methods section and eMethods 2 in Supplement 1.
c
Variant detected in secondary analysis.