39% overall yield in 244 bilateral SNHL patients; highest yields in congenital-onset cases
Yield: 39%
Literature Review
Curated evidence supporting genetic testing indications
189 peer-reviewed references organized by organ system, each with diagnostic yields and key findings extracted from the published literature. Every entry has been reviewed for relevance to exome and genome sequencing clinical decision-making.
Strong (134)
Moderate (55)
Emerging (0)
Browse by Organ System
21 systems with associated literature. Select a system to jump to its references.
Auditory/Hearing
11 references
67% yield using stepwise approach (GJB2 first, then CMA, then targeted panel) in 423 children with SNHL
Yield: 67%
Genetic screening of 591 Italian RP/Usher probands achieved 37.4-55.2% diagnostic yield across subtypes
Yield: 37.4-55.2%
25% diagnostic yield in 2183 rare disease families; monogenic disorders 35% vs complex 11%; ID/hearing/vision 40-55%; trios had highest yield; 14% required research+automated combined approaches
Yield: 25%
Stepwise genetic strategy achieved 73% overall yield for hearing loss: hotspot screening then WES for remaining
Yield: 73%
Comprehensive genomic panel testing identified genetic cause in 44% of 474 children with hearing loss
Yield: 44%
ES achieved 47.2% diagnostic yield for childhood hearing loss, with higher yield (52.5%) in pediatric-onset cases
Yield: 47.2%
WES identified causative variants in 21.1% of Portuguese SNHL patients, expanding European hearing loss variant spectrum
Yield: 21.1%
WES-based reanalysis after negative hearing loss panel identified STRC copy number variants as significant contributor to NSHL
NGS panel identified causative variants in 48% of childhood SNHL cases in Spanish cohort
Yield: 48%
GS detected CNVs in 17% of hearing loss patients who were negative on prior ES, demonstrating added value of GS
Yield: 17%
Cardiovascular
11 references
Strong
WES covers >98% of variants identified by targeted cardiac gene panels, supporting exome as a comprehensive alternative
Exome sequencing achieved 66.7% diagnostic yield in infantile heart failure, identifying genetic causes of cardiomyopathy
Yield: 66.7%
25% diagnostic yield in 2183 rare disease families; monogenic disorders 35% vs complex 11%; ID/hearing/vision 40-55%; trios had highest yield; 14% required research+automated combined approaches
Yield: 25%
32% genetic cause identified in 528 children with cardiomyopathy; infants <1 year less likely to have molecular diagnosis
Yield: 32%
Combined cardiomyopathy and arrhythmia genetic testing yielded 19.9% positive rate in 4782 patients, supporting comprehensive cardiac panels over siloed testing
Yield: 19.9%
39.6% diagnostic yield in pediatric cardiomyopathy, 61% of diagnoses missed by cardiac gene panels
Yield: 39.6%
29.3% GS diagnostic yield in 744 families with undiagnosed rare diseases; 8.2% required GS specifically (intronic, SVs, repeat expansions); 53.4% of post-exome diagnoses were from exome reanalysis alone
Yield: 29.3%
28.7% overall diagnostic yield with CMA + trio-WES for CHD; 61.5% in syndromic vs 17.3% in isolated CHD
Yield: 28.7%
Moderate
NGS retesting yielded 20% additional diagnoses in previously negative inherited arrhythmia and cardiomyopathy patients
Yield: 20%
NGS approaches for pediatric cardiovascular disease demonstrate high diagnostic yield, particularly for congenital heart defects with extracardiac features
WGS achieved 30% diagnostic yield in patients with suspected monogenic stroke, identifying both known and novel pathogenic variants
Yield: 30%
Connective Tissue
3 references
17.1% diagnostic yield with 32-gene panel in 199 hereditary aortopathy patients (FBN1, TGFBR1/2, SMAD3, COL3A1)
Yield: 17.1%
18% pathogenic variants in 226 nonsyndromic HTAAD probands; genetic findings predict disease severity
Yield: 18%
Mutations in 16 genes spanning Marfan, EDS subtypes, OI in 34 patients with heritable connective tissue disorders
Craniofacial
3 references
37.5% diagnostic yield with exome/WGS in 56 craniosynostosis patients; FGFR2, FGFR3, TWIST1, TCF12 most common
Yield: 37.5%
14-15% overall diagnostic yield in 309 craniosynostosis patients; single-suture majority of referrals
Yield: 14-15%
84% molecular diagnostic rate in 89 children with syndromic craniosynostosis using clinical criteria + NGS
Yield: 84%
Dermatologic
10 references
RASopathies NGS panel with functional analysis improved diagnostic yield from 31.7% to 36.5%
Yield: 36.5%
58% diagnostic yield in 343 individuals with mosaic skin disorders; variants detected at allele frequencies as low as 1%
Yield: 58%
88% diagnostic yield with RNA sequencing in 40 families with inherited skin disorders unresolved by DNA testing
Yield: 88%
WES enables molecular subtyping and differential diagnosis in clinically overlapping EDS presentations
NOD2 targeted sequencing identified Blau syndrome in 21.1% of patients initially diagnosed with JIA
Yield: 21.1%
Deep sequencing detects somatic mosaicism in PIK3CA-related overgrowth spectrum not found by standard sequencing
94-95% diagnostic yield in 308 epidermolysis bullosa cases with NGS panel (COL7A1, KRT5, KRT14, LAMB3, LAMA3)
Yield: 94-95%
Comprehensive review of genetic causes of vascular malformations across PI3K/AKT/mTOR and RAS/MAPK pathways
KLK15 gene variants identified as potential molecular basis for hypermobile EDS
GNA11 R183C somatic mosaicism identified across a spectrum of capillary malformation phenotypes in 17 patients
Developmental
25 references
2025 AAP guidelines: ~80% yield in severe ID, ~20% in mild ID, higher yields with dysmorphic features or neurological comorbidities
Yield: 20-80%
DDD Study achieved 41% diagnostic yield using combined clinical and computational approaches with trio exome sequencing
Yield: 41%
Clinical exome sequencing yielded 26% overall molecular diagnosis in 814 consecutively referred patients; trio-CES 31% vs proband-CES 22%; developmental delay in children 41%
Yield: 26%
36.8% diagnostic yield in consanguineous NDD families by ES; identified 30 novel candidate genes
Yield: 36.8%
41% diagnostic yield for duo/quad/trio and 28% for singleton WES in NDD cohort using semiautomated workflow
Yield: 41%
Meta-analysis of 37 studies establishes ES as first-tier test for NDDs with 36% pooled diagnostic yield, surpassing CMA (15-20%)
Yield: 36%
Exome sequencing identified a genetic diagnosis in 29% of NIHF cases after standard workup was nondiagnostic, many involving metabolic etiologies
Yield: 29%
Meta-analysis of 103 studies/32,331 individuals: overall 23.7% yield; epilepsy 24%, ASD 17.1%, ID 28.2%; exome 27.2% vs panel 22.6%
Yield: 23.7%
32.7% ES yield in pediatric cerebral palsy lab referral cohort (n=1345), 10.5% in healthcare-based adult cohort; comorbid ID+epilepsy+ASD reached 32.9%; variants in 229 genes
Yield: 32.7%
Trio ES in 1790 NDD patients achieved 49.8% diagnostic yield with de novo variants accounting for >80% of diagnoses
Yield: 49.8%
ACMG recommends ES/GS as first-tier or early-tier test for congenital anomalies and developmental delay/intellectual disability, with 30-40% diagnostic yields
Yield: 30-40%
Strong
CES as first-tier test achieved 55% overall diagnostic yield in 128 pediatric patients; 64% for metabolic and 81% for hyperlipidemia indications
Yield: 55%
25% diagnostic yield in 2183 rare disease families; monogenic disorders 35% vs complex 11%; ID/hearing/vision 40-55%; trios had highest yield; 14% required research+automated combined approaches
Yield: 25%
32.5% diagnostic yield in 1000 UAE/Middle East patients; 62% autosomal recessive; high consanguinity contributed to unique genetic landscape
Yield: 32.5%
31.5% diagnostic yield with proband-only ES in large Indian NDD cohort; consanguinity associated with higher yield
Yield: 31.5%
Meta-analysis showed 31.1% diagnostic yield of NGS in cerebral palsy, establishing genetic testing as standard workup for CP
Yield: 31.1%
Genome sequencing yielded 7.8% diagnostic rate in 1612 ASD quartets and 46.1% in 295 fetal structural anomaly cases
Yield: 7.8%
Deep sequencing detects somatic mosaicism in PIK3CA-related overgrowth spectrum not found by standard sequencing
Trio-exome sequencing showed 26-34% diagnostic yield for GDD/ID when combining CMA and clinical exome sequencing
Yield: 26-34%
Genetic determinants of global developmental delay and intellectual disability in Ukrainian children
Strong
15.8% diagnostic yield in 417 Ukrainian children with GDD/ID; WES 59.4% yield vs gene panel 12.1% yield, demonstrating superiority of broad sequencing
Yield: 15.8%
2.6% additional CNV diagnostic yield from exome data across 6,633 rare disease families (15,759 individuals)
Yield: 2.6%
29.3% GS diagnostic yield in 744 families with undiagnosed rare diseases; 8.2% required GS specifically (intronic, SVs, repeat expansions); 53.4% of post-exome diagnoses were from exome reanalysis alone
Yield: 29.3%
Moderate
Genome sequencing as first-tier test achieved 21% diagnostic yield in GDD/ID, detecting variants missed by exome including SVs and intronic variants
Yield: 21%
Systematic exome re-analysis in 1040 NDD patients yielded 2.3% additional diagnoses beyond initial analysis, leveraging updated gene-disease knowledge
Yield: 2.3%
NGS approaches for pediatric cardiovascular disease demonstrate high diagnostic yield, particularly for congenital heart defects with extracardiac features
Endocrine
15 references
Endocrine Society guidelines recommend CYP21A2 genotyping when hormonal testing is equivocal or for genetic counseling
Exome sequencing achieved 35% likely genetic diagnosis in 46,XY DSD patients (22.5% pathogenic + 12.5% likely pathogenic variants)
Yield: 35%
28.1% diagnostic yield with targeted NGS panel for DSD (vs 10% with single gene tests), plus 15.6% VUS
Yield: 28.1%
59.3% molecular diagnosis for 46,XY DSD; 78.9% overall when combined with clinical/biochemical classification
Yield: 59.3%
>90-95% of CAH cases caused by 10 common CYP21A2 mutations, allowing genotype-phenotype correlation
Yield: >90%
34.9% diagnostic yield from ES in pediatric endocrine cohort including growth disorders, DSD, and adrenal conditions
Yield: 34.9%
NGS panels and ES increasingly applied across endocrine disorders including thyroid, adrenal, pituitary, and reproductive endocrinology
PPP2R3C biallelic variants cause novel syndromic 46,XY gonadal dysgenesis in 4 girls from 4 families; extragonadal anomalies include hearing loss and dysmorphism
Comprehensive review of genomic tools for DSD diagnosis including CMA, ES, GS and their clinical implementation challenges
Comprehensive review of non-coding regulatory elements in mammalian sex determination, focusing on SOX9 enhancers and SRY regulatory regions
Survey of 26 European centers managing 6720 DSD/CHH patients showed wide variation in genetic testing approaches with diagnostic yields ranging from 7-60% depending on phenotype and test type
Yield: 7-60%
Novel AR gene variant identified by WES in CAIS patient with 46,XY karyotype
Panel testing for congenital hypogonadotropic hypogonadism: current approaches and future directions
Moderate
Review of 14-gene NHS panel testing for congenital hypogonadotropic hypogonadism, addressing oligogenic inheritance and diagnostic challenges
WES identified 22 variants in 6 genes across 21 patients with 46,XY DSDs
Yield: ~100%
24% molecular diagnostic yield using WES and SNP-array in 75 Turkish patients with short stature
Yield: 24%
Gastrointestinal
5 references
25-52% diagnostic yield for suspected genetic disorders with exome sequencing; trio testing improved rates by 16 percentage points
Yield: 25-52%
VEO-IBD has high rate of monogenic etiology requiring integrated genomic and immunologic evaluation
WES identified CARMIL2 deficiency as monogenic cause of VEO-IBD with combined immunodeficiency
WES discovered novel NLRP3 gain-of-function variant as cause of VEO-IBD with autoinflammation
ESPGHAN recommends NGS with targeted panel for very early-onset IBD (<6 years); monogenic causes in 15-20% of cases
Yield: 15-20%
Hematologic/Lymphatic
13 references
RAS pathway somatic variants characterized in 938 patients with disorders of somatic mosaicism including vascular malformations
Strong
68.5% somatic variant detection using targeted NGS panel for arteriovenous malformation evaluation
Yield: 68.5%
62.4% PIK3CA variant detection rate in largest cohort of disorders of somatic mosaicism to date (n=1197)
Yield: 62.4%
80.8% somatic variant detection rate using high-depth targeted NGS in vascular malformation tissue
Yield: 80.8%
47% pathogenic variant detection rate using targeted NGS panel on vascular anomaly tissue specimens
Yield: 47%
Comprehensive review of PIK3CA-related overgrowth spectrum with focus on vascular and lymphatic manifestations and emerging targeted therapies
Cell-free DNA NGS liquid biopsy detects somatic variants in arteriovenous malformations from peripheral blood samples
Moderate
Cell-free DNA next-generation sequencing successfully detects IDH1 somatic variant in Maffucci syndrome from peripheral blood
Molecular characterization of sporadic venous malformations identifies TEK/TIE2 and PIK3CA somatic variants as primary drivers
Comprehensive review of genetic causes of vascular malformations across PI3K/AKT/mTOR and RAS/MAPK pathways
Somatic second-hit mutations identified in HHT lesional tissue supporting two-hit model for telangiectasia and AVM formation
GNA11 R183C somatic mosaicism identified across a spectrum of capillary malformation phenotypes in 17 patients
Comprehensive genomic profiling identifies PIK3CA somatic variants in overgrowth disorders with vascular components
Hematology/Oncology
3 references
9.0% pathogenic/likely pathogenic variant prevalence across 29 genes in first 10,000 patients for cancer panel testing
Yield: 9.0%
5% pathogenic/likely pathogenic rate in broad referral population with accessible delivery model for hereditary cancer risk
Yield: 5%
Panel-based approaches maintain comparable diagnostic yield to exome for hereditary cancer in pediatric oncology
Hepatic/Liver
5 references
NGS panel for cholestatic liver diseases achieved 32.4% diagnostic yield identifying genetic cholestasis subtypes
Yield: 32.4%
~25% diagnostic yield with WES in 19 adults with unexplained chronic liver disease including late-presenting genetic cholestasis
Yield: 25%
60% detection rate for neonatal cholestasis with targeted NGS panel (SERPINA1, JAG1, ATP8B1, ABCB11)
Yield: 60%
Tiered genetic testing approach with panel followed by WES achieves high diagnostic yield in pediatric liver diseases
31% diagnostic yield with WES in 166 children with unexplained liver disease; 42% in cholestatic, 38% in metabolic
Yield: 31%
Immunologic
16 references
VEO-IBD has high rate of monogenic etiology requiring integrated genomic and immunologic evaluation
WES identified CARMIL2 deficiency as monogenic cause of VEO-IBD with combined immunodeficiency
Systematic review: 15-79% diagnostic yield across 36 NGS studies in PID; higher in consanguineous populations
Yield: 15-79%
WES achieved 70% diagnostic yield in consanguineous PID population, highest among IEI genomic studies
Yield: 70%
39% diagnostic yield for CNVs in 97 PID patients by CMA; 22q11.2 deletion most common
Yield: 39%
WES discovered novel NLRP3 gain-of-function variant as cause of VEO-IBD with autoinflammation
Systematic review of NGS for PIDs shows average 29% diagnostic yield across studies (range 10-79%)
Yield: 10-79%
15.3% diagnostic rate in 294 sporadic PID patients by WES; novel variants in CTLA4, STAT3, PIK3CD
Yield: 15.3%
24.6% yield in pediatric and 9% in adult PID patients (Dutch cohort of 254)
Yield: 24.6%
Strong
CMA supplementing ES for IEI achieved 40.4% combined yield; CMA detected CNVs in 5.4% missed by ES
Yield: 40.4%
NOD2 targeted sequencing identified Blau syndrome in 21.1% of patients initially diagnosed with JIA
Yield: 21.1%
Systematic exome reanalysis of 1300 IEI patients yielded additional 15.2% diagnoses beyond initial analysis
Yield: 15.2%
NGS achieved 32.48% diagnostic yield in Mexican IEI cohort of 157 patients, expanding known variants in Latin American populations
Yield: 32.48%
77.9% diagnostic yield in Turkish IEI cohort of 417 patients undergoing genetic testing, among highest reported
Yield: 77.9%
WES achieved 50% diagnostic yield in Thai pediatric IEI cohort, identifying both known and novel variants
Yield: 50%
Combined genome sequencing and RNA-seq achieved 14% diagnostic yield for IEI, detecting variants missed by exome alone
Yield: 14%
Metabolic/Biochemical
11 references
RNA-seq transcriptomics provides 10-35% additional diagnostic yield beyond WES alone for inborn errors of metabolism
Yield: 10-35%
89% concordance between PEARS enzymatic assay and molecular testing for PKU in 89 patients
Yield: 89%
88% (15/17) of metabolic disorders confirmed by exome sequencing in NC NEXUS newborn screening project
Yield: 88%
Exome sequencing identified a genetic diagnosis in 29% of NIHF cases after standard workup was nondiagnostic, many involving metabolic etiologies
Yield: 29%
Strong
CES as first-tier test achieved 55% overall diagnostic yield in 128 pediatric patients; 64% for metabolic and 81% for hyperlipidemia indications
Yield: 55%
25% diagnostic yield in 2183 rare disease families; monogenic disorders 35% vs complex 11%; ID/hearing/vision 40-55%; trios had highest yield; 14% required research+automated combined approaches
Yield: 25%
89.6% diagnostic yield in 67 pediatric leukodystrophy patients using panels and WES; 24 genes identified
Yield: 89.6%
29.3% GS diagnostic yield in 744 families with undiagnosed rare diseases; 8.2% required GS specifically (intronic, SVs, repeat expansions); 53.4% of post-exome diagnoses were from exome reanalysis alone
Yield: 29.3%
WES diagnostic yield ranges 16-68% across IEM and neurogenetic disorder cohorts depending on clinical selection
Yield: 16-68%
NGS achieved 64.3% diagnostic yield for IEM in Lebanese population; WES yielded 49% for mitochondrial disorders
Yield: 64.3%
WES/WGS has substantially improved diagnostic yield for leukodystrophies; proposed classification system integrates genetic and pathological findings
Musculoskeletal
18 references
RASopathies NGS panel with functional analysis improved diagnostic yield from 31.7% to 36.5%
Yield: 36.5%
Strong
52% overall diagnostic yield (64% in pediatric, 35% in unspecified myopathies) at Slovenian tertiary center
Yield: 52%
WES enables molecular subtyping and differential diagnosis in clinically overlapping EDS presentations
74% genetic diagnostic yield in 34 pediatric patients with hyperCKaemia without overt muscle weakness
Yield: 74%
70% diagnostic yield with exome sequencing in 43 Thai pediatric muscular disorder patients, identifying 36 pathogenic variants in 14 genes
Yield: 70%
CNVs from exome data contribute ~7% of solved cases across movement disorders, muscle disorders and neuropathies in 4800 patients
Yield: 7%
NOD2 targeted sequencing identified Blau syndrome in 21.1% of patients initially diagnosed with JIA
Yield: 21.1%
Strong
Mitochondrial disease gene variants identified as common cause of inherited peripheral neuropathies across 2087 patients with neuropathy phenotypes
2.6% additional CNV diagnostic yield from exome data across 6,633 rare disease families (15,759 individuals)
Yield: 2.6%
65.2% diagnostic yield with WES in 46 previously unsolved muscular disorder patients from a Taiwanese pediatric cohort of 161
Yield: 65.2%
29.3% GS diagnostic yield in 744 families with undiagnosed rare diseases; 8.2% required GS specifically (intronic, SVs, repeat expansions); 53.4% of post-exome diagnoses were from exome reanalysis alone
Yield: 29.3%
Recurrent ITPR3 p.Thr1424Met variant identified in 33 affected individuals from 9 unrelated CMT1 families across multiple populations; mutational hotspot with dominant-negative mechanism
LGMD most prevalent hereditary myopathy in Saudi adults; 68% diagnostic yield; WES sensitivity 46% underscoring need for complementary approaches
Yield: 68%
VWA1 variants identified in 20 patients with autosomal recessive neuropathy; 11 novel variants; carrier frequency ~1/441 in UK; may account for 1% of unexplained hereditary neuropathies
69.6% diagnostic yield with NGS in 135 Thai pediatric neuromuscular disorder patients; inherited myopathies 70.7%, neuropathies 63.3%, CMS 90%
Yield: 69.6%
46% diagnostic yield with targeted NGS panel in 146 patients with myopathy or muscular dystrophy
Yield: 46%
~50% solved rate in 61 South African patients with inherited neuropathies and hereditary spastic paraplegia
Yield: 50%
KLK15 gene variants identified as potential molecular basis for hypermobile EDS
Nephrology/Renal
11 references
9% monogenic causes in adults with suspected inherited kidney disease; diagnostic utility extends beyond classic presentations
Yield: 9%
43% diagnostic yield for familial kidney disease (58/135 families), 81% for Alport, 80% for tubular disorders
Yield: 43%
95% detection rate with NGS of COL4A3/4/5 genes for Alport syndrome; expert consensus guidelines
Yield: 95%
NGS panel achieved 42.1% diagnostic yield in 1001 Chinese children with renal disease, identifying 106 distinct monogenic renal disorders
Yield: 42.1%
Genomic testing achieved 39% diagnostic yield in 204 patients with kidney disease of unknown etiology; changed management in 59% of diagnosed cases
Yield: 39%
Mayo Clinic Nephrology Genomics Clinic achieved 30.7% diagnostic yield in 163 patients with suspected genetic kidney disease
Yield: 30.7%
80% diagnostic yield for Alport syndrome in individuals with hematuria and family history; guidelines for genetic testing and management
Yield: 80%
Guidelines recommend genetic testing as key diagnostic test for persistent hematuria, proteinuria, or kidney failure of unknown origin
A Next-Generation Sequencing Approach to the Diagnosis of Chronic Kidney Disease of Unknown Etiology
Moderate
NGS approaches are increasingly identifying monogenic causes in previously undiagnosed CKD, with diagnostic yields of 10-40% across studies
Exome sequencing identified genetic diagnoses in 42% of adults with CKD in a Saudi Arabian cohort
Yield: 42%
Exome sequencing identified genetic diagnoses in 15% overall (30% in non-African ancestry) of 128 patients with presumed hypertensive nephropathy
Yield: 15%
Neurological
28 references
19% diagnostic yield for exome sequencing in unexplained pediatric epilepsy (100/522), 61% of diagnoses in genes not on standard epilepsy panels
Yield: 19%
Early-life epilepsies and the emerging role of genetic testing
Clinical exome sequencing yielded 26% overall molecular diagnosis in 814 consecutively referred patients; trio-CES 31% vs proband-CES 22%; developmental delay in children 41%
Yield: 26%
38.2% positive/likely positive DES yield in epilepsy patients (vs 28.7% without epilepsy); epileptic encephalopathies highest at 43.4%; novel genes added 7% yield
Yield: 38.2%
RASopathies NGS panel with functional analysis improved diagnostic yield from 31.7% to 36.5%
Yield: 36.5%
Meta-analysis of 37 studies establishes ES as first-tier test for NDDs with 36% pooled diagnostic yield, surpassing CMA (15-20%)
Yield: 36%
58% diagnostic yield with WES/WGS in early-onset epilepsy with suspected genetic etiology in population-based study
Yield: 58%
Meta-analysis of 103 studies/32,331 individuals: overall 23.7% yield; epilepsy 24%, ASD 17.1%, ID 28.2%; exome 27.2% vs panel 22.6%
Yield: 23.7%
32.7% ES yield in pediatric cerebral palsy lab referral cohort (n=1345), 10.5% in healthcare-based adult cohort; comorbid ID+epilepsy+ASD reached 32.9%; variants in 229 genes
Yield: 32.7%
25% diagnostic yield in 2183 rare disease families; monogenic disorders 35% vs complex 11%; ID/hearing/vision 40-55%; trios had highest yield; 14% required research+automated combined approaches
Yield: 25%
72% diagnostic yield (86% including novel genes) in 246 Turkish children from 190 consanguineous families; 82% homozygous variants; 52% would be missed on gene panels
Yield: 72%
32.5% diagnostic yield in 1000 UAE/Middle East patients; 62% autosomal recessive; high consanguinity contributed to unique genetic landscape
Yield: 32.5%
CNVs from exome data contribute ~7% of solved cases across movement disorders, muscle disorders and neuropathies in 4800 patients
Yield: 7%
Meta-analysis showed 31.1% diagnostic yield of NGS in cerebral palsy, establishing genetic testing as standard workup for CP
Yield: 31.1%
43% diagnostic yield in infantile epilepsy (Gene-STEPS), 74% in neonatal-onset seizures vs 36% infantile-onset
Yield: 43%
Genetic determinants of global developmental delay and intellectual disability in Ukrainian children
Strong
15.8% diagnostic yield in 417 Ukrainian children with GDD/ID; WES 59.4% yield vs gene panel 12.1% yield, demonstrating superiority of broad sequencing
Yield: 15.8%
Strong
Mitochondrial disease gene variants identified as common cause of inherited peripheral neuropathies across 2087 patients with neuropathy phenotypes
2.6% additional CNV diagnostic yield from exome data across 6,633 rare disease families (15,759 individuals)
Yield: 2.6%
29.3% GS diagnostic yield in 744 families with undiagnosed rare diseases; 8.2% required GS specifically (intronic, SVs, repeat expansions); 53.4% of post-exome diagnoses were from exome reanalysis alone
Yield: 29.3%
Recurrent ITPR3 p.Thr1424Met variant identified in 33 affected individuals from 9 unrelated CMT1 families across multiple populations; mutational hotspot with dominant-negative mechanism
VWA1 variants identified in 20 patients with autosomal recessive neuropathy; 11 novel variants; carrier frequency ~1/441 in UK; may account for 1% of unexplained hereditary neuropathies
46% diagnostic yield in ciliopathy (Joubert/Meckel-Gruber) families with exome sequencing enhanced by split-read CNV screening
Yield: 46%
WES diagnostic yield ranges 16-68% across IEM and neurogenetic disorder cohorts depending on clinical selection
Yield: 16-68%
Systematic exome re-analysis in 1040 NDD patients yielded 2.3% additional diagnoses beyond initial analysis, leveraging updated gene-disease knowledge
Yield: 2.3%
~50% solved rate in 61 South African patients with inherited neuropathies and hereditary spastic paraplegia
Yield: 50%
WES/WGS has substantially improved diagnostic yield for leukodystrophies; proposed classification system integrates genetic and pathological findings
WGS achieved 30% diagnostic yield in patients with suspected monogenic stroke, identifying both known and novel pathogenic variants
Yield: 30%
Whole exome sequencing identifies somatic mosaic variants in focal cortical dysplasia type III brain lesion tissue
Ophthalmic
7 references
Genetic screening of 591 Italian RP/Usher probands achieved 37.4-55.2% diagnostic yield across subtypes
Yield: 37.4-55.2%
25% diagnostic yield in 2183 rare disease families; monogenic disorders 35% vs complex 11%; ID/hearing/vision 40-55%; trios had highest yield; 14% required research+automated combined approaches
Yield: 25%
70-80% diagnostic yield with targeted IRD panels, rising to 92% with WGS as second tier
Yield: 70-92%
62.9% initial ES diagnostic yield + 8.3% additional from clinician-driven reanalysis in 264 Korean IRD patients; total 71.2%
Yield: 71.2%
28.8% WGS yield in 66 WES-negative IRD families; true added value 9.6% overall (only 1.5% if CNV pipeline already applied to WES)
Yield: 28.8%
49.2% diagnostic yield in 506 IRD probands with panel testing; 69 genes, ABCA4/USH2A/RPGR most frequent
Yield: 49.2%
3/3 previously unsolved IRD cases solved with long-read GS (PacBio Revio): deep intronic USH2A variant, large EYS deletion, compound het; demonstrates utility of long-read technology
Yield: 100%
Psychiatric/Behavioral
8 references
36.8% diagnostic yield in consanguineous NDD families by ES; identified 30 novel candidate genes
Yield: 36.8%
41% diagnostic yield for duo/quad/trio and 28% for singleton WES in NDD cohort using semiautomated workflow
Yield: 41%
Meta-analysis of 103 studies/32,331 individuals: overall 23.7% yield; epilepsy 24%, ASD 17.1%, ID 28.2%; exome 27.2% vs panel 22.6%
Yield: 23.7%
31.5% diagnostic yield with proband-only ES in large Indian NDD cohort; consanguinity associated with higher yield
Yield: 31.5%
Genome sequencing yielded 7.8% diagnostic rate in 1612 ASD quartets and 46.1% in 295 fetal structural anomaly cases
Yield: 7.8%
20.5% diagnostic rate in trio-based WES of 220 ASD probands; de novo variants in CHD8, SHANK3, SCN2A most recurrent
Yield: 20.5%
57% diagnostic yield with WES in 405 children with NDD from consanguineous families; 189 genes including novel candidates
Yield: 57%
8.6-17% yield in 151 patients with epilepsy and psychiatric comorbidity depending on modality (CMA vs panel vs WES)
Yield: 8.6-17%
Pulmonary
7 references
Extended genetic panels (>12 genes) for PCD achieved 80% sensitivity; 54.8-93.9% yield depending on genes and del/dup analysis
Yield: 80%
76% overall diagnostic yield combining WES with targeted CNV analysis in 45 PCD families
Yield: 76%
Strong
70% diagnostic yield with targeted NGS panel in 33 Egyptian PCD families, identifying variants in 12 known PCD genes
Yield: 70%
4.1% definitive diagnostic yield across 416 subjects with ILD, mucociliary clearance disorders, and pulmonary vascular disease
Yield: 4.1%
46.8% baseline yield in 496 PCD families; noncoding variant analysis added 38.1% yield in 42 previously unsolved cases
Yield: 46.8%
42% diagnostic yield for PCD using targeted exome capture and novel bioinformatics filtering in a 20-patient PCD subset
Yield: 42%
46% diagnostic yield in ciliopathy (Joubert/Meckel-Gruber) families with exome sequencing enhanced by split-read CNV screening
Yield: 46%
Reproductive
21 references
Exome sequencing achieved 35% likely genetic diagnosis in 46,XY DSD patients (22.5% pathogenic + 12.5% likely pathogenic variants)
Yield: 35%
1-1.5% monogenic diagnostic rate in 1,112 infertile men; idiopathic male infertility highly polygenic
Yield: 1-1.5%
Exome analysis of 147 patients with maturation arrest spermatogenic failure identified 5 novel candidate genes; genetic diagnosis has pre-TESE prognostic implications
23% diagnostic yield from WES in non-obstructive azoospermia cohort; identified pathogenic variants in known and novel infertility genes
Yield: 23%
12.71% Y-chromosome microdeletion rate in 6,806 men with non-obstructive azoospermia; AZFc most common
Yield: 12.71%
WES identified homozygous FSHR variant as cause of primary ovarian failure in consanguineous family
De novo SRY R75M mutation identified by trio WES causing 46,XY complete gonadal dysgenesis; functional studies confirmed loss of DNA-binding activity
Exome sequencing identified 3 novel NR5A1 mutations in 4 DSD patients with broad phenotypic spectrum from gonadal dysgenesis to spermatogenic failure
PPP2R3C biallelic variants cause novel syndromic 46,XY gonadal dysgenesis in 4 girls from 4 families; extragonadal anomalies include hearing loss and dysmorphism
Comprehensive review of genomic tools for DSD diagnosis including CMA, ES, GS and their clinical implementation challenges
WES identified a novel NR5A1 missense variant causing 46,XX sex reversal in an Iranian family
Comprehensive review of non-coding regulatory elements in mammalian sex determination, focusing on SOX9 enhancers and SRY regulatory regions
40-60% diagnostic yield for targeted gene panels in specific male infertility conditions; ES/GS expanding discovery of novel genes
Yield: 40-60%
CMA and FISH in 38 cases of 46,XX testicular DSD showed high breakpoint variability; ARSE gene deletion associated with short stature phenotype
Survey of 26 European centers managing 6720 DSD/CHH patients showed wide variation in genetic testing approaches with diagnostic yields ranging from 7-60% depending on phenotype and test type
Yield: 7-60%
Novel AR gene variant identified by WES in CAIS patient with 46,XY karyotype
CFTR mutations identified in 58% of CAVD cohort by WES
Yield: 58%
WES identified AR gene mutation in a CAIS family with testicular malignant tumors, highlighting cancer risk in retained gonads
WES discovered FIGNL1 as novel gene causing ovarian dysgenesis and primary ovarian insufficiency
WES identified 22 variants in 6 genes across 21 patients with 46,XY DSDs
Yield: ~100%
Moderate
Karyotyping, CNV-seq, QF-PCR and WES identified genetic causes in 4 Chinese DSD patients with diverse clinical presentations
Skeletal
15 references
97% mutation detection in OI type I and 99% in moderate-to-severe OI using gene panel testing (598 patients)
Yield: 97-99%
Diagnostic strategies and genotype-phenotype correlation in large Indian OI cohort
77% molecular diagnostic yield in a rare skeletal dysplasia cohort of 114 patients using comprehensive genomic approaches
Yield: 77%
42% diagnostic yield in 543 skeletal dysplasia patients, 58% in fetal cases vs 39% postnatal; 71 genes, 49.3% contributing uniquely
Yield: 42%
40% diagnostic yield using rapid exome sequencing in critically ill children, with highest yields in skeletal dysplasia cases
Yield: 40%
40.4% diagnostic yield using exome sequencing for fetuses presenting with short long bones on ultrasound
Yield: 40.4%
69% pooled diagnostic yield from systematic review of ES for fetal skeletal dysplasia across 226 cases
Yield: 69%
Pooled diagnostic yield of 60.2% for prenatal exome sequencing in fetal skeletal abnormalities across 524 cases
Yield: 60.2%
50% molecular diagnostic yield for skeletal dysplasia in 262 patients evaluated through Slovenian national health system
Yield: 50%
57.9% molecular diagnostic yield for fetal skeletal dysplasia using comprehensive genetic testing in 152 Chinese fetuses
Yield: 57.9%
96% detection rate using exome sequencing and gene panels for prenatal skeletal dysplasia screening in 118 cases
Yield: 96%
65.79% diagnostic yield using whole exome sequencing for fetal skeletal dysplasia in 38 cases
Yield: 65.79%
31.1% diagnostic yield using trio prenatal ES with enhanced splice and mitochondrial variant analysis in 90 fetuses
Yield: 31.1%
50% molecular diagnostic yield for fetal skeletal dysplasia using genetic testing in 24 cases from Wuhan
Yield: 50%
24% molecular diagnostic yield using WES and SNP-array in 75 Turkish patients with short stature
Yield: 24%