Table 3.

Summary of health and clinical outcomes in 36 case series studies with ≥20 patients.

Authors	Publication year	Country	Timing	N	Indication	Inclusion	Exclusion	ES or GS	Clinical management outcomes	Reproductive outcomes	Behavioral or psychosocial outcomes	Harms
Anazi et al.17	2017	Saudi Arabia	NR	232	ID	Documented IQ ≤ 70; children <5 years w/physician-assessed DD/ID	NR	ES	1 pt started on chelation tx w/excellent response in terms of manganese level	NR	NR	NR
Baldridge et al.24	2017	USA	3/2012–1/2015	155	CA	NR	NR	ES	84/155, 54%: additional dx studies (molecular, imaging, biochem); 8/155, 0.6%: clin mgmt directly impacted (change in med, surg procedures, referrals to specialists); 36/155, 23%: enrolled in research studies	NR	NR	2/155, 1%: cases of nonpaternity requiring ethics consultation and altered strategies for pretest couns
Bekheirnia et al.34	2017	USA	NR	112 (62 families)	CA	Pts w/nonsyndromic forms of CAKUT; pts w/syndromic forms of CAKUT w/o identified genetic etiology	Pts w/syndromic forms of CAKUT w/known genetic etiology; pts w/nonsyndromic and nonfamilial forms of VUR	ES	3/62, 5% families: pt mgmt changed: 1/62, 2% families: pt tapered on immunosuppressants; 1/62, 2% families: pt referred for hearing screening; 1/62, 2% families: pt referred to ophthalm w/specialty in genetic disorders, evals found congenital optic nerve abnormalities	NR	NR	NR
Bick et al.42	2017	USA	2010–2013	22	CA/DD/ID	Pts w/std dx testing; apparently undiagnosed monogenic genetic disorder; molecular dx thought to aid physicians/families w/med decision-making/mgmt or fam planning; sufficient samples to undertake genomic testing & follow-up testing as needed; cost of GS appeared less costly than testing individual genes for phenotype	NR	GS	6/22, 27%: change in pt mgmt. (in total): 4/22, 18%: medication change/initiation/supported use of; 6/22, 27%: screening/testing/surveillance	8/22, 36%: reported as risk of recurrence for parents	NR	NR
Bourchany et al.35	2017	France	NR	29	CA/DD/ID	Undiagnosed DD/ID and (1) an ongoing preg of at-risk relatives requesting genetic couns; (2) hospitalization in an ICU w/a diagnostic request for guiding care	NR	ES	5/29, 17%: changed pt mgmt. (total): 2/29, 7%: added med; 1/29, 3%: investigated systemic involvement; 2/29, 7%: inclusion in a clin trial	12/29, 41%: enabled prenatal couns/testing; 13/29, 45%: enabled reproductive planning; 12/29, 41%: enabled prenatal couns/testing; 2/29, 7%: used prenatal dx in subsequent pregnancies to have unaffected fetuses	NR	NR
Cordoba et al.39	2018	Argentina	NR	40	CA/DD/ID	Consecutive series of 40 pts selected for ES from a neurogenetic clinic of a tertiary hospital; presence of typical findings of known neurogenetic diseases and/or hints of monogenic etiology such as familial aggregation or chronic and progressive course	NR	ES	13/40, 32.5%: change pt mgmt. (in total): 4/40, 10%: trial of new med; 2/40, 5%: avoid specific drugs; 1/40, 3%: monitoring for hypogonadism	NR	NR	NR
Dixon-Salazar et al.16	2012	Middle East/North Africa/Central Asia	NR	118	CA/DD/ID	NR	NR	ES	1/118, 0.1%: re-eval of pt‘s fam for GJC2-assoc disease; 1/118, 0.1%: MAN2B1 variant pt care redirected & provided fam guidance; 1/118, 0.1%: withdrew vitamin E tx	10/118, 8%: genetic couns, prenatal dx options, and carrier testing were altered after dx	NR	NR
Evers et al.36	2017	Germany	1/2013–12/2015	72	CA/DD/ID	Pts w/DD/ID and/or CA; pts w/infantile dystonia; pts w/neurometabolic disorder	NR	ES	8/72, 11% change pt mgmt (in total): 2/72, 3%: change of antiepileptic med in 1 pt, tx w/galactose in 1 pt; 6/72, 8%: initiated surveillance for other disease-associ complications	4/60, 7% families: decision to undergo additional fetal testing; in 20/21, 95%: families who received reports: the result was important for fam planning, either w/regard to a further preg of the parents or for the future fam planning of their nonaffected children	NR	NR
Farnaes et al.20	2018	USA	7/2016–3/2017	42	CA	Inpatient; <1 year of age; no etiologic dx; possible genetic disease	>1 year of age; discharged/deceased; dx likely to be obtained via clin testing; sx determined not likely to be due to a genetic etiology; parents unavail/refused consent	GS	5/42, 12%: med change; 4/42, 10%: change in surg; 1/42, 2%: palliative care initiated; 4/42, 10%: change in imaging/procedure; 10/42, 24%: morbidity avoided (comparison to historical/controls); 1/42, 2%: 83–94% decrease in mortality risk compared with historical/control	NR	NR	NR
French et al.14	2019	UK	12/2016–9/2018	195	CA	CA; neuro sx; suspected metabolic disease; surg necrotizing enterocolitis; extreme IUGR; or failure to thrive; unexplained critical illness/clinician request	Prematurity w/o additional features; known trisomies or other genetic dx; trauma; hematological malignancy/oncology; bronchiolitis/respiratory tract infection	GS	35/195, 18%: change pt mgmt. (in total); 7/195, 4%: initiated palliative care; 5/195, 3%: modified tx; 19/195, 10%: initiated new specialist care; 14/195, 7%: informed existing specialist care	7/195, 4%: informed subsequent reproductive decisions; 14/195, 7%: informed parents of significant recurrence risk	NR	NR
Iglesias et al.26	2014	USA	10/2011–7/2013	115	CA/DD/ID	Pts clinically evaluated by one of three board-certified clin geneticists and one of six board-certified genetic counselors	NR	ES	20/115, 17%: change pt mgmt (in total): 3/115, 3%: medication/dietary change/optimization; 3/115, 3%: eval for additional disorders; 2/115, 2%: screening of at-risk fam; 1/115, 1%: provided enrollment information for clin trial; 2/115, 2%: terminated additional/invasive testing; 4/115, 3%: referral to social services/MDA, educational placement/planning, early intervention	6/115, 5%: “fam planning” including: 3/115, 3%: decision to use PGD in subsequent preg; 1/115, 1%: CVS was undertaken; others not specified	NR	NR
Kuperberg et al.31	2016	Israel	2011–2015	57	CA/DD/ID	Pts of MAGEN clinic suspected as having a monogenic disorder, undiagnosed despite extensive clin, biochem, imaging, and traditional genetic evals, including karyotype, CMA testing for duplicated or deleted segments or for areas of excessive homozygosity, candidate gene sequencing, biopsy if possible, metabolic workup and others as deemed required	NR	ES	4/57, 7%: immediate change in medication due to ES results; 1/57, 2%: change to ketogenic diet; 2/57, 4%: at-risk fam members underwent genetic testing	2/57, 4%; pregnant mothers underwent additional fetal testing; 29/57, 51%: families had more accurate genetic counseling	NR	NR
Meng et al.8	2017	USA	2011–2017	278	CA	Age ≤100 days of life at time of testing; referred for ES from December 2011 to January 2017; underwent ES performed as clin service	NR	ES	53/278, 19%: change pt mgmt (in total): 19/53, 36% pts w/change in mgmt: palliative/withdrawal of life support; 7/53, 13%: initiation/change of medication/diet; 5/53, 9%: initiation/change of procedures; 27/53, 51%: referral to specialists; 21/278, 8%: identification of carrier status/other disorders/risk for disorders	90 (88.2%) families: genetic counseling	NR	NR
Miller et al.37	2017	UK	NR	40	CA	Pts w/craniosynostosis; previously investigated by molecular genetic testing with normal findings	Pts w/targeted genetic testing identifying a monogenic cause; pts for whom enrollment into Deciphering Devel Disorders study was considered more appropriate; samples not avail for analysis	ES (n = 37), GS (n = 3)	7/40, 18%: total change in pt mgmt; 1/40, 3%: commenced prophylactic azithromycin and itraconazol; 1/40, 3%: lifelong monitoring for progressive aortic dilatation; 1/40, 3%: recommendation for coagulation screening prior to any future surg; 1/40, 3%: regular monitoring for secondary complications incl. cardiovascular disease and diabetes; 1/40, 3%: underwent detailed immunological assessment & awaiting donor for stem cell transplant; 1/40, 3%: underwent detailed endocrinology assessment; 1/40, 3%: referral to a clin psych and dietitian to address her eating behaviors	1/40, 3%: parents considering not to have more children after dx of pt; 1/40, 3%: enrolled in prenatal genetic dx program	NR	NR
Nair et al.19	2018	Lebanon	2015–2017	167	CA/DD/ID	Ped pts referred for genetic couns by PCP	NR	ES	1/167, 0.6%: fam members of pt w/ACMG59 variant assoc w/sudden death underwent screening & were referred to cardiac specialist for follow-up	NR	NR	NR
Nolan and Carlson32	2016	USA	6/2011–6/2015	53	CA/DD/ID	Pts evaluated in the ped neuro clinic referred for ES	Pts w/out ES	ES	12/53, 23% changed pt mgmt (in total): 5/53, 9%; medication/drug management; 1/53, 2%; neuroimaging frequency; 1/53, 2%: enrollment in clin trial; 2/53, 4%; testing for pt‘s sibling; 6/53, 11%: referrals to: nephr, cardio, ophthalm, multidisciplinary, hematology, audiology, pulmonology; 1/53, 2%: pt's father referred to cardio	10/53, 19%: impacted fam planning (not otherwise specified)	1/53, 2%: referral to support groups	NR
Perucca et al.38	2017	Australia	NR	40	CA	Pts prospectively enrolled from routine clin practice w/MRI-negative focal epilepsy and a fam hx of febrile seizures or any type of epilepsy in at least one first- or second-degree relative	Pts w/previous genetic testing, severe ID and benign focal epilepsies of childhood	ES	1/40, 3%: stopped presurg eval; 1/40, 3%: started on perampanel, discontinued carbamazepine	NR	NR	NR
Petrikin et al.41	2018	USA	10/2014–6/2016; follow-up until 11/2016	32 (rapid GS + std genetic tests); N = 5 compassionate crossover from std group	CA	Infants age <4 months in NICU/PICU w/illnesses of unknown etiology; genetic test order or genetic consult; major structural CA or ≥3 minor anomalies; abnormal lab test suggesting a genetic disease; abnormal response to standard tx for a major underlying condition	Pts w/previously confirmed genetic dx explaining clin condition; features pathognomonic for a chromosomal aberration	GS	7/37, 19%: change other than counseling (total); 4/37, 11%: change in subspecialty consult; 1/37, 3%: change in medication; 2/37, 5%: change in procedure; 1/37, 3%: change in diet; 3/37, 8%: change in imaging	10/37, 27%: genetic or reproductive counseling (not specified)	NR	NR
Powis et al.47	2018	USA	NR	66	CA/DD/ID	Neonatal (birth–1 mo) pt samples sent for ES at clin lab	NR	ES	1/66, 2%: patient found to have SOX10 variant; fam withdrew ventilator support, pt expired	1/66, 2%: mother of pt underwent prenatal testing in subsequent preg, fetus not found to have pathogenic variant & was delivered healthy	NR	NR
Sawyer et al.15	2016	Canada	NR	N = 105 families	CA	Pts enrolled in FORGE project	NR	ES	6/105, 6% families: 3 pts tx adjusted; 3 pts tx initiated	NR	NR	NR
Soden et al.27	2014	USA	NR	119	CA/DD/ID	Families w/heterogeneous clin conditions	NR	ES, GS	12/119, 10%: new med/dietary tx; 5/119, 4%: stopped current med/dietary tx; 18/119, 15%: added or changed procedures relating to dx; 1/119, 0.8%: cardio exam for mother of proband	NR	NR	NR
Scocchia et al.11	2019	Mexico	NR	60	CA/DD/ID	Pts presenting for Illumina iHope prog: referral from ped to dysmorphology clinic for eval of CA/suspected genetic disorder; clin genetics eval w/med hx, 3 generation pedigree, phys exam; financial hardship precluding appropriate genetic testing	Pts w/isolated feature; acquired disease, pts w/clin dx of specific genetic disease, discharged from clinic	GS	8/60, 13%: referral to specialists; 3/60, 5%: avoided muscle biopsy; 3/60, 5%: underwent add’l clinical investigation; 1/60, 2%: transition to palliative care	37/60, 62%: impact on preconception testing/PGD	NR	NR
Srivastava et al.28	2014	USA	11/2011–2/2014	78	DD/ID	Pts presenting to ped neurogenetics clinic at Kennedy Krieger Institute for etiological eval of previously unexplained neurodevel disorders, including DD/ID, CP, and ASD	NR	ES	5/78, 6%: discontinued meds; 2/78, 3%: added medications; 4/78, 5%: started disease monitoring; 6/78, 8%: investigated systemic involvement; 3/78, 4%: provided info for clin trials	27/78, 35%: impact on reproductive planning (not otherwise specified)	NR	NR
Stark et al.7	2016	Australia	2/2014–5/2015	80	CA	Infant (≤2 years); multiple CA and dysmorphic features; other features of monogenic disorder (e.g., neurometabolic, renal, eye)	Pts w/CNV responsible for phenotype; previous single-gene testing; single-gene disorder unlikely; disorder caused by known gene unlikely	ES	9/80, 11%: surveillance for other conditions; 1/80, 1%: stopped surveillance; 2/80, 3%: decision not to undergo muscle biopsy; 1/80, 1%: change of surg approach; 2/80, 3%: rationalized current tx; 3/80, 4%: change of mgmt (NOS); 12/80, 15%: fam members diagnosed through cascade testing w/identification of carrier status/other disorders/risk for disorders (e.g., ACMG v2.0)	3/80, 4%: used prenatal dx for subsequent preg; 28/80, 35%: now considered “high risk” for future pregnancies	NR	NR
Stark et al.23	2018	Australia	4/2016–9/2017	40	CA	Pts aged 0–18 yrs w/likely monogenic disorder; mult organ syst involved, severe condition w/complexity and/or high acuity	Pts w/CNV responsible for phenotype; previous single-gene testing; single-gene disorder unlikely; secure clinical dx of a monogenic disorder (e.g., Apert, CHARGE syndromes)	ES	Mortality: n = 9, 23%; change in mgmt overall: 14/40, 35%; med. started/adjusted, n = 4; med. stopped, n = 1; surveillance initiated, n = 7; avoidance of tissue biopsy, n = 3; redirection to palliative care, n = 2; provided info for clinical trial, n = 1	NR	NR	NR
Tammimies et al.25	2015	Canada	2008–2013	95	CA/DD/ID	Pts consecutively referred from 2008 to 2013 from devel ped clinics that perform multidisciplinary team assessments for ASD	NR	ES	6/95, 6% findings were deemed med actionable	NR	NR	NR
Tan et al.43	2017	Australia	5/2015–11/2015	44	CA	Ambulant children aged 2–18 years; w/ suspected monogenic condition; nondiagnostic SNP microarray	Pts w/suspected disorder that would usually be made by clin assessment; any prior single-gene or panel sequencing test; pts deemed to have novel phenotypes precluding derivation of a reasonable differential dx list	ES	6/44, 14%: altered clin mgmt; 1/44, 2%: had dx tests canceled	1/44, 2%: pt‘s parents planned to use PGD	NR	NR
Tarailo-Graovac et al.33	2016	Canada	10/2012–1/2015	41	CA/DD/ID	Consecutively enrolled pts w/confirmed or potential DD/ID disorder; metabolic phenotype of unknown cause after extensive previous metabolic or genetic testing	Confirmed dx of teratogen exposure; congenital infection; autoimmune disorder; pathogenic CNV; withdrawal from study	ES	11/41, 27%: Initiation/change of med; 3/41, 7%: initiation/change of screening patterns; 2/41, 5%: initiation/change of procedures; 5/41, 12%: initiation/change of dietary modifications	NR	NR	NR
Thevenon et al.40	2016	France	NR	43	CA/DD/ID	Pts w/absence of a strong dx hypothesis after clin eval; negative dx workup including array-CGH, fragile X screening, targeted testing for single-gene disorders	Pts w/malformative features suggesting syndromic etiology; suspicion of an acquired disorder	ES	4/43, 9%: change in clin mgmt (in total); coenzyme Q10 supplementation was introduced (20 mg/kg/day) and ketogenic diet has been evoked as the forthcoming therapeutic alternative	2/43, 5%: pts’ diagnoses enabled two prenatal diagnoses for parents in subsequent pregnancies	NR	NR
Thiffault et al.45	2018	USA	2015–2017	80	CA/DD/ID	NR	NR	ES	6/80, 8% (total) change of pt mgmt.; 1/80, 1%: care withdrawn; 1/80, 1%: pt transitioned to TSC clinic; 4/80, 5%: Identification of carrier status/other disorders/risk for disorders (e.g., ACMG v2.0)	NR	NR	NR
Todd et al.41	2015	Australia	NR	38	CA	Dx w/FADS, arthrogryposis, or a severe congenital myopathy	NR	ES	1/38, 3%: pt & his father had clin mgmt changes, but it does not state what that was	1/38, 3%: mother of pt w/CHRND variant underwent PGD & subsequently terminated preg w/affected fetus	NR	NR
Valencia et al.48	2015	USA	NR	40	CA/DD/ID	NR	NR	ES	9/40, 23%: change in clin mgmt (in total); 8/40, 20%: ended dx odyssey; 2/40, 5%: specific follow-up studies recommended; 3/40, 8%: surveillance recommended; 5/40, 13%: targeted tx/sx tx/new mgmt plan; 1/40, 3%: med concerns for fam members	14/40, 35%: “informative genetic couns” provided, not otherwise specified	NR	NR
van Diemen et al.46	2017	Netherlands	NR	23	CA	Age <1 at presentation with 1+ CA and/or severe neuro sx, such as intractable seizures, suggestive of a genetic cause of the disease	Pts w/clear indications for specific syndrome that could be tested by targeted analysis of known genes or structural variations; not critically ill; no consent to rapid targeted genomics test	GS	5/23, 22%: withdrawal of unsuccessful intensive care tx	2/23, 9%, pts’ parents changed their mind about NOT having additional children after learning of avail prenatal genetic testing; 1/23, 4% decided to undergo PGD (unclear if performed)	NR	NR
Vissers et al.18	2017	Netherlands	2011–2015; follow-up: min. 6 mos (median: 17 mos) (range: 6–42 mos) after starting ES	150	CA/DD/ID	Consecutive pts w/(nonacute) neuro sx of suspected genetic origin	Pts w/well-known, clinically easily recognizable genetic disorders	ES	1/150, 0.7%: antiepileptic drug changed; comp w/standard genetic testing pathway: 36/150, (24%) pts the dx process would have been limited to ES and no invasive/additional procedures performed	NR	NR	NR
Willig et al.22	2015	USA	2011–2014	35	CA	Parent–child trios enrolled in a research biorepository who had GS and standard dx tests to diagnose monogenic disorders of unknown cause	Infants likely to have disorders assoc w/cytogenetic abnormalities w/positive findings on prior testing	120-day mortality: w/genetic dx 12/21, 57% vs. no genetic dx 2/14, 14%; p = 0.46; 15/35, 43% (total): change in pt mgmt; 6/15, 40%: palliative care initiated; 3/15, 20%: imaging change; 4/15, 27%: initiation/change of med; 2/15, 13%: initiation/change of diet; 1/15, 7%: specific surg. undertaken b/c of dx result	4/35, 11%: nonspecified genetic/reproductive couns change	NR	NR	NR
Zhu et al.30	2015	USA, Israel	NR	119	CA/DD/ID	NR	NR	ES	2/119 trios, 2%: change of med leading to impr outcomes for patients; 2/119 trios, 2%: initiation/change of dietary mod	NR	NR	NR

ACMG American College of Medical Genetics and Genomics, ASD autism spectrum disorder, assoc associated, avail available, b/c because, biochem biochemical, CA congenital anomalies, CAKUT congenital abnormalities of the kidney and urethral tract, cardio cardiology/cardiologist, CGH (array) comparative genomic hybridization, clin clinical, CMA chromosomal microarray, CNV copy-number variant, comp comparison, couns counseling, CP cerebral palsy, CVS chorionic villus sampling, DD developmental delay, devel developmental, dx diagnostic/diagnosis, ES exome sequencing, eval evaluation, FADS fetal akinesia deformation sequence, fam family, GS genome sequencing, hx history, ICU intensive care unit, ID intellectual disability, impr improved/improvement, IUGR intrauterine growth restriction, lab laboratory, MAGEN a metabolic-neurogenetic multidisciplinary clinic at Wolfson Medical Center in Israel, med medical/medication(s), mgmt management, mod modification(s), mo(s) months, MRI magnetic resonance image, mult multiple, nephr nephrology, neuro neurological, NICU neonatal intensive care unit, NOS not otherwise specified, NR not reported, ophthalm ophthalmologist, PCP primary care provider/physician, ped pediatric, PGD preimplantation genetic diagnosis, PICU pediatric intensive care unity, Preg pregnancy, psych psychology/psychologist, pt(s) patient(s), SNP single-nucleotide polymorphism, std standard, surg surgery/surgical, sx symptoms, TSC tuberous sclerosis complex, tx treatment/therapy, VUR vesicoureteral reflux, w/ with, w/o without, yr(s) year(s).