Table 2. Eighteen molecular diagnoses made by whole-genome sequencing only, in 17 study participants.
| ID | Primary HPO terms | Sex | Gene | IP | Genomic variant(s) (zygosity) [transcript] | OMIM diagnosis (phenotype no.) | Reason not detected by conventional testing |
|---|---|---|---|---|---|---|---|
| Case 1 | Focal segmental glomerulosclerosis | Female | PLCE1 | AR | c.553C>T p.(Arg185*) (hom) [NM_001165979.1]a | Nephrotic syndrome, type 3 (610725) | Gene not tested |
| Case 3 | Ocular albinism | Male | GPR143 | XL | c.885+748G>A (hem) [NM_000273.2]a,b | Ocular albinism, type I, Nettleship-Falls type (300500) | Deep intronic variant |
| Case 5 | Rod-cone dystrophy; microcephaly; short stature; cognitive impairment; abnormality of epiphysis morphology | Male | RNU4ATAC | AR | n.13C>G; n.29T>C; in trans [NR_023343.1]b | Roifman syndrome (616651) | Gene not tested |
| Case 11 | Global developmental delay; episodic metabolic acidosis; abnormal thalamic MRI signal intensity | Female | SLC25A19 | AR | c.495G>A p.(Met165Ile) (het) [NM_001126122.1] chr17:(73,267,001-73,271,500)x1b | Thiamine metabolism dysfunction syndrome 4 (613710) | Gene not tested |
| Case 27 | Global developmental delay; seizures; central hypotonia; brain atrophy | Male | PIGA | XL | c.290T>A p.(Met97Lys) (hem) [NM_002641.3] | Multiple congenital anomalies–hypotonia–seizures syndrome 2 (300868) | Gene not tested |
| Case 32c | Seizures; global developmental delay | Male | MED23 | AR | c.1919A>G p.(Gln640Arg) (hom) [NM_004830.3] | Mental retardation, autosomal recessive 18 (614249) | Gene not tested |
| Case 33 | Global developmental delay; deafness; chorea; spasticity | Male | BCAP31 | XL | c.332_335dupTGCT p.(Ser113Alafs*6) (hem) [NM_001139441.1] | Deafness, dystonia, and cerebral hypomyelination (300475) | Gene not tested |
| Case 34 | Hemolytic uremic syndrome | Female | DGKE | AR | c.494A>G p.(Asp165Gly) (hom) [NM_003647.2] | Nephrotic syndrome, type 7 (615008) | Gene not tested |
| Case 36 | Intellectual disability; seizures; generalized hypotonia; abnormal facial shape; short stature | Female | ANKRD11 LGI1 | AD | c.2512C>T p.(Arg838*) (het) [NM_013275.5] AD c.1096G>A p.(Gly366Arg) (het) [NM_005097.2] | KBG syndrome (148050) Epilepsy, familial temporal lobe, 1 (600512) | Gene not tested Gene not tested |
| Case 43 | Global developmental delay; spasticity; microcephaly | Male | CTNNB1 | AD | c.1041_1044delATCT p.(Val349Alafs*9) (het) [NM_001904.3]d | Mental retardation, autosomal dominant 19 (615075) | Gene not tested |
| Case 45 | Hyperammonemia; abnormality of ornithine metabolism | Female | OTC | XL | c.540+265G>A (het) [NM_000531.5]a,b | Ornithine transcarbamylase deficiency (311250) | Deep intronic variant |
| Case 64 | Global developmental delay; muscular hypotonia; febrile seizures; decreased activity of mitochondrial complex II | Male | PIGG | AR | c.2600_2601delTA p.(Leu867*) (hom) [NM_017733.3]e | Mental retardation, autosomal recessive 53 (616917) | Gene not well characterized at time of testing |
| Case 74 | Global developmental delay; seizures; generalized hypotonia; myopathy; microcephaly | Male | UNC13A | AR | c.154G>A p.(Glu52Lys) (hom) [NM_001080421.2]e | NA 30 | Gene not well characterized at time of testing |
| Case 86 | Global developmental delay; seizures; CNS hypomyelination | Female | SLC35A2 | XL | c.991G>A p.(Val331Ile) (het) [NM_005660.1]a,d | Congenital disorder of glycosylation, type IIm (300896) | Gene not tested |
| Case 107 | Global developmental delay; seizures; generalized hypotonia | Female | TBL1XR1 | AD | c.1337A>G p.(Tyr446Cys) (het) [NM_024665.4]a,d | Mental retardation, autosomal dominant 41 (616944) | Gene not tested |
| Case 111 | Microcephaly; global developmental delay | Female | TRIO | AD | c.4311+1G>A (het) [NM_007118.2]d | Mental retardation, autosomal dominant 44 (617061) | Gene not tested |
| Case 112 | Ciliary dyskinesia | Male | HYDIN | AR | c.10368-2A>G (het); c.[8674C>G;8675delA] p.(Gln2892Glyfs*3) (het); in trans [NM_001270974.1] | Primary ciliary dyskinesia 5 (608647) | Gene not tested |
AD, autosomal dominant; AR, autosomal recessive; CNS, central nervous system; hem, hemizygous; het, heterozygous; hom, homozygous; HPO, Human Phenotype Ontology; IP, inheritance pattern; Mi, mitochondrial; MRI, magnetic resonance imaging; NA, not available; XL, X-linked.
b
Variant(s) not detected with research-based WES (see text for details).
c
Case is described in detail elsewhere.40
d
De novo variant (if not indicated for an autosomal dominant gene, then parental sample(s) were unavailable).
e
Initially highlighted as a variant of uncertain significance on clinical WES.