Table 2.
Clinical impact of critical trio exome in 32 patients received diagnosis
| ID | Gender | Age at testing (days) |
Exome sequencing TAT (days) |
Gene(s) | Disease(s) | Inheritance pattern |
Variants | Zygosity | Status | Impact on Clinical Management |
Exome sequencing as first-tier test |
Exome sequencing returned before discharge/death |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1002 | M | 57 | 11 | NPHP3 | Nephronophthisis 3 [MIM:604387]; Renal-hepatic-pancreatic dysplasia 1 [MIM:208540] | AR | c.1928C>T (p.P643L), c.2694–2_2694–1delAG | compound het | Alive | Cardiology follow up for mild aortic valve stenosis and mildly hypoplastic pulmonary valve annulus | Y | Y |
| 1004 | M | 18 | 14 | HSD17B4 | D-bifunctional protein deficiency [MIM:261515]; Perrault syndrome 1 [MIM:233400] | AR | c.1210–11C>G, c.936_937delTA (p.T313*) | compound het | Alive | Endocrinology evaluation for adrenal insufficiency; audiology and gastroenterology referral | Y | N |
| 1005 | M | 5 | 9 | DYNC2H1 | Short-rib thoracic dysplasia 3 with or without polydactyly [MIM:613091] | AR | c.10594C>T (p.R3532*), c.9814T>A (p.L3272I) | compound het | Alive | Follow up for renal, hepatic, pancreatic and ocular disease for future concerns | Y | Y |
| 1006 | M | 9 | 10 | FANCA | Fanconi anemia, complementation group A [MIM:227650] | AR | c.154C>T (p.R52*), c.2852G>A (p.R951Q) | compound het | Alive | Bone marrow transplant for Fanconi anemia | Yes, concurrent with breakage studies | Y |
| 1007 | M | 81 | 15 | UNC13D | Hemophagocytic lymphohistiocytosis, familial, 3 [MIM:608898] | AR | c.118–308C>T (N/A), c.2346_2349delGGAG (p.R782fs) | compound het | Alive | Bone marrow transplant for hemophagocytic lymphohistiocytosis | Yes, concurrent with CMA | Y |
| 1008 | M | 10 | 12 | ACAD9 | Mitochondrial complex I deficiency due to ACAD9 deficiency [MIM:611126] | AR | c.163C>T (p.P55S), c.860G>A (p.G287E) | compound het | Alive | Follow up with Cardiology; Riboflavin | Y | N |
| 1009 | M | 89 | 14 | LIPT1 | Lipoyltransferase 1 deficiency [MIM:616299] | AR | c.212C>T (p.S71F), c.539T>C (p.L180S) | compound het | Alive | Redirection of care | Y | Y |
| 1011 | M | 26 | 9 | KLHL40 | Nemaline myopathy 8, autosomal recessive [MIM:615348] | AR | c.472_475delCGCT (p.A158fs), c.1153–2A>T | compound het | Alive | N/A | Y | Y |
| 1012 | M | 91 | 14 | SLC4A11 | Corneal dystrophy, Fuchs endothelial, 4 [MIM:613268] | AR | c.1040G>A (p.R347Q), c.1855G>A (p.A619T) | compound het | Alive | N/A | N | Y |
| 1013 | F | 34 | 13 | COL12A1 | Ullrich congenital muscular dystrophy-2 [MIM: 616470]; Bethlem myopathy 2 [MIM:616471]. | AR | c.5794+2T>A (N/A), c.5269C>T (p.R1757*) | compound het | Alive | N/A | Yes, concurrent PWS, SMA and Trio WES | Y |
| 1014 | M | 34 | 13 | CASK | FG syndrome 4 [MIM:300422]; Mental retardation and microcephaly with pontine and cerebellar hypoplasia [MIM:300749] | XL | c.1721dupA (p.S575fs) | de novo hemi | Alive | Redirection of care | Y | Y |
| 1015 | M | 7 | 12 | EFTUD2 | Mandibulofacial dysostosis, Guion-Almeida type [MIM:610536] | AD | c.869+1G>C | de novo het | Alive | Audiology in addition to multiple subspecialties already involved in care | Y | Y |
| 1016 | M | 97 | 14 | SMARCA4 | Coffin-Siris syndrome 4 [MIM:614609] | AD | c.2936G>A (p.R979Q) | de novo het | Alive | N/A | N | Y |
| 1024 | M | 7 | 14 | CHD7 | CHARGE syndrome [MIM:214800] | AD | c.7234G>T (p.E2412X) | de novo het | Alive | Ophthalmology and Immunology evaluation | Y | Y |
| 1026 | M | 18 | 19 | KCNQ2 | Epileptic encephalopathy, early infantile, 7 [MIM:613720]; Seizures, benign familial neonatal 1 (BFNS1) | AD | c.1742G>A (p.R581Q) | de novo het | Alive | Developmental therapies initiated sooner due to association with EIEE7 and BFNE | Y | N |
| 1030 | M | 11 | 13 | KMT2D | Kabuki syndrome 1 [MIM:147920] | AD | c.13040_13041del ( p.Q4347fs) | de novo het | Alive | Immunology and Ophthalmology evaluation | N | N |
| 1052 | M | 4 | 17 | Xp22.31p22.33 loss | XL | chrX:181779–8997440 loss | Inherited hemi | Alive | initiating endocrine work up-found to have hypogonadotropic hypogonadism; mother previously had multiple miscarriages-found to carry the deletion | Yes, concurrent with CMA | Y | |
| 1104 | F | 7 | 10 | KLHL24 | Epidermolysis bullosa (EB) | AD | c.1A>G (p.M1?) | de novo het | Alive | Facilitated appropriate management by Dermatology for newly described (2016) epidermolysis bullosa simplex form | Y | N |
| 1105 | M | 36 | 15 | WNT5A | Robinow syndrome, autosomal dominant 1 [MIM:180700] | AR | c.496C>T (p.R166C) | homo | Alive | N/A | N | N |
| 1106 | F | 10 | 14 | MUT | Methylmalonic aciduria, mut(0) type [MIM:251000] | AR | c.422C>A (p.A141E) | homo | Alive | Pro-Phree/Propimex-1 formula and carnitine | Yes, concurrent with metabolic panels | Y |
| 1108 | M | 58 | 17 | ACTC1 | Left ventricular noncompaction 4; Cardiomyopathy, dilated, 1R [MIM:613424]; Cardiomyopathy, hypertrophic, 11 [MIM:612098]; Atrial septal defect 5 [MIM:612794] | AD | c.635G>A (p.R212H) | Inherited het (from father) | Alive | Orthotopic heart transplant for left ventricular non-compaction cardiomyopathy | Yes, concurrent with CMA | Y |
| 1111 | F | 7 | 19 | BRCA2 | Fanconi anemia, complementation group D1 [MIM:605724]; Breast-ovarian cancer, familial, 2 [MIM:612555] | AR | c.4965C>G (p.Y1655*), c.7007G>C (p.R2336P) | compound het | Deceased | N/A (see notes) | Yes, concurrent with CMA | Y |
| 1116 | F | 15 | 13 | TRMU | Liver failure, transient infantile [MIM:613070] | AR | c.117G>A (p.W39*), c.680G>C (p.R227T) | compound het | Deceased | Redirection of care | N | N |
| 1173 | F | 83 | 13 | FAT4 | Van Maldergem syndrome 2 (VMLDS2) [MIM:615546] | AR | c.739C>A (p.P247T), c.2486T>G (p.L829R) | compound het | Alive | Audiology evaluation, in addition to multiple subspecialties already involved in care | Y | Y |
| 1198 | F | 14 | 13 | ETFDH | Glutaric acidemia IIC [MIM:231680] | AR | c.405+3A>G (N/A), c.739G>C (p.G247R) | compound het | Deceased | Treated with Carbaglu (carglumic acid) and Riboflavin; Redirection of care | N | Y |
| 1202 | F | 14 | 10 | ENPP1 | arterial calcification of infancy, generalized, 1 (GACI1) [MIM: 208000] | AR | c.913C>A (p.P305T); c.2246C>G (p.S749*) | compound het | Deceased | Treated with pamidronate; Redirection of care | Y | Y |
| 1204 | M | 50 | 13 | PTPN11 | LEOPARD syndrome 1 [MIM:151100]; Metachondromatosis [MIM:156250]; Noonan syndrome 1 [MIM:163950] | AD | c.1528C>G (p.Q510E) | de novo het | Deceased | N/A | Yes, concurrent with CMA | Y |
| 1207 | M | 6 | 15 | DYNC1H1 | Mental retardation, autosomal dominant 13 [MIM:614563] | AD | c.6074G>A (p.R2025Q) | de novo het | Deceased | N/A | Yes, concurrent with CMA | N |
| KMT2C | Kleefstra syndrome [MIM: 610253] | AD | c.4513A>G (p.I1505V) | de novo het | ||||||||
| 1209 | M | 86 | 24 | OFD1 | Joubert syndrome 10 [MIM:300804]; Orofaciodigital syndrome I [MIM:311200] | XL | c.604_609del (p.E202_Y203del) | Inherited hemi | Deceased | Redirection of care | N | N |
| 1210 | M | 32 | 9 | GBE1 | Glycogen storage disease IV [MIM:232500] | AR | c.1239delT (p.D413fs) | homo | Deceased | Redirection of care | Yes, concurrent with CMA | N |
| 1217 | M | 7 | 13 | 8p23.3p23.1 loss; 12p13.33p13.31 gain | Unbalanced translocation | AD | chr8:190907 – 8234192 loss; chr12:234929 – 8376765 gain |
de novo het | Deceased | N/A | Yes, concurrent with CMA | Y |
| 1226 | M | 43 | 13 | 11q23.3q25 gain;22q11.1q11.21 gain | Emmanuel syndrome | AD | chr11:116691675–134889485 gain; chr22:17072086–20130474 gain | de novo het | Deceased | Redirection of care | N | N |
Notes: While there was no direct clinical impact on the infant, cascade testing directly affecting parental health was relevant
Het: heterozygous; Hemi: hemizygous; homo: homozygous