Top 99 Genetic Causes of Developmental Delay Panel

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy Genes Gene CPT Codes Copy CPT Codes
12675 ACTB 81479,81479 Order Options
ADNP 81479,81479
AHDC1 81479,81479
ANKRD11 81479,81479
ARID1A 81479,81479
ARID1B 81479,81479
ASH1L 81479,81479
ASXL3 81479,81479
ATP1A3 81479,81479
ATRX 81479,81479
AUTS2 81479,81479
BRAF 81406,81479
BRPF1 81479,81479
CACNA1A 81185,81479
CASK 81479,81479
CDK13 81479,81479
CDKL5 81406,81405
CHAMP1 81479,81479
CHD2 81479,81479
CHD7 81407,81479
CHD8 81479,81479
CREBBP 81407,81406
CTCF 81479,81479
CTNNB1 81479,81479
DDX3X 81479,81479
DHCR7 81405,81479
DNMT3A 81479,81479
DYNC1H1 81479,81479
DYRK1A 81479,81479
EBF3 81479,81479
EFTUD2 81479,81479
EHMT1 81479,81479
EP300 81479,81479
FOXG1 81404,81479
FOXP1 81479,81479
GABRA1 81479,81479
GABRB3 81479,81479
GNAO1 81479,81479
GRIN2B 81479,81479
HDAC8 81479,81479
HNRNPU 81479,81479
HUWE1 81479,81479
IQSEC2 81479,81479
ITPR1 81479,81479
KANSL1 81479,81479
KAT6A 81479,81479
KAT6B 81479,81479
KCNB1 81479,81479
KCNQ2 81406,81479
KDM5C 81407,81479
KDM6A 81479,81479
KIF1A 81479,81479
KMT2A 81479,81479
KMT2D 81479,81479
MECP2 81302,81304
MED12 81479,81479
MED13L 81479,81479
MEF2C 81479,81479
MTOR 81479,81479
MYT1L 81479,81479
NAA10 81479,81479
NALCN 81479,81479
NF1 81408,81479
NR2F1 81479,81479
NSD1 81406,81405
OPHN1 81479,81479
PACS1 81479,81479
POGZ 81479,81479
PPP2R5D 81479,81479
PTEN 81321,81323
PTPN11 81406,81479
PURA 81479,81479
RAI1 81405,81479
RIT1 81479,81479
RPS6KA3 81479,81479
SATB2 81479,81479
SCN1A 81407,81479
SCN2A 81479,81479
SCN8A 81479,81479
SETD5 81479,81479
SHANK3 81479,81479
SLC2A1 81405,81479
SLC6A1 81479,81479
SMARCA2 81479,81479
SMARCA4 81479,81479
SMC1A 81479,81479
SPTAN1 81479,81479
STXBP1 81406,81479
SYNGAP1 81479,81479
TBL1XR1 81479,81479
TCF4 81406,81405
TRIO 81479,81479
UBE3A 81406,81479
USP9X 81479,81479
VPS13B 81408,81407
WAC 81479,81479
WDR45 81479,81479
ZC4H2 81479,81479
ZEB2 81405,81404
Test Code Test Copy Genes Panel CPT Code Gene CPT Codes Copy CPT Code Base Price
12675 Genes x (99) 81479 81185, 81302, 81304, 81321, 81323, 81404, 81405, 81406, 81407, 81408, 81479 $990 Order Options

Pricing Comments

We are happy to accommodate requests for testing single genes in this panel or a subset of these genes. The price will remain the list price. If desired, free reflex testing to remaining genes on panel is available. Alternatively, a single gene or subset of genes can also be ordered via our PGxome Custom Panel tool.

A 25% additional charge will be applied to STAT orders. View STAT turnaround times here.

For Reflex to PGxome pricing click here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

Turnaround Time

18 days on average

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

Developmental delay can describe any youth who is not meeting typical milestones in one or more of the following areas: physical, cognitive, communication, social/emotional, or adaptive development. Developmental delays are common: In a typical classroom of 30 students, ~ 5 will have a developmental disability (DD), according to a recent Center for Disease Control and Prevention survey of parents (Zablotsky et al. 2019. PubMed ID: 31558576). Patients with developmental delays may benefit from an early molecular diagnosis of the cause of their delay in order to receive specialty treatments or access to patient support groups. Families may benefit from diagnosis for prognostic information, and future family planning decisions. Testing this panel of 99 genes provides a low-cost opportunity to diagnose the most common genetic causes of developmental delay at an early age.

Genetics

Many developmental disabilities are suspected to be genetic in origin (~40%), yet will go undiagnosed for years due to the high cost of genetic testing, among other barriers. This financial burden stems from the enormous diversity of genes known to cause DDs, and the broad differential diagnosis for most children with delays. While trio whole exome/genome sequencing is likely to be the most effective test for diagnosis, its high cost limits accessibility. In order to make genetic testing available to more children, we sought to determine which genes account for the greatest number of diagnoses in patients with DD. We reasoned that sequencing a smaller number of genes would reduce cost, thus increasing accessibility.

Therefore, we curated this list of 99 genes that account for the largest number of developmental delay diagnoses. To develop this list, we used information from three sources: 1) Exome-level data from >1,500 PreventionGenetics patients with DD, ~300 positive cases, 2) Published and unpublished DD cohorts - including the Deciphering Developmental Disorders study, the CAUSES study, and data from other large clinical labs (see references section for published cohorts included), and 3) Variant tallies from the Human Gene Mutation Database (HGMD) and Clinvar database of disease-causing variants. We first calculated a “Gene Score” for predicted diagnostic yield for DD based on numbers of diagnoses across cohorts (formula = [Sum of LP/P diagnoses in NNNN gene across six cohorts analyzed] + [Sum of cohorts with a LP/P case for NNNN gene]). Sum of cohorts with a diagnosis in NNNN gene was included in the score to address possible cohort-specific biases, by giving additional weight to genes with diagnoses well-spread across cohorts (i.e. a gene with a single diagnosis in each of six cohorts would be scored higher than a gene with six diagnoses in a single cohort). Gene score values in our study ranged from 35 for ARID1B - with 29 total diagnoses, and positive ARID1B-related Coffin-Siris cases observed in all six cohorts analyzed (29 + 6 = 35), down to 4 (i.e. two total diagnoses in MAGEL2 were observed in two of the six cohorts analyzed, 2+2 = 4). After including all genes on the list with a gene score of 7 or higher (observed in ≥ two studies, and ≥ four patients with developmental delays within those studies), we picked genes 88-99 within the lower-range of gene-scores, based on combined frequency of database entries in ClinVar and HGMD. To summarize, we created a list of 99 genes with the highest predicted diagnostic yield for DDs.

Ranking at the top, the most-common causes of DD include ARID1B - Coffin Siris syndrome, ANKRD11 - KBG syndrome, KMT2A - Wiedemann Steiner syndrome, KMT2D - Kabuki syndrome, MECP2 - Rett syndrome, SYNGAP1 - AD intellectual disability type 5, BRPF1 - intellectual developmental disorder with dysmorphic facies and ptosis, DDX3X - X-linked intellectual disability type 102. These 8 genes account for 15% of positive DD diagnoses at PreventionGenetics. In total, the 99 genes on this panel account for over 50% of PG positive findings in patients with developmental disabilities (not explained by large copy number variants). Genes with autosomal dominant or X-linked inheritance and frequent de novo occurrences top the list.

We hope this panel will increase accessibility to genetic testing for the ~17% of the population affected by a developmental disability.

Testing Strategy

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 99.0% average coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing.

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).

Clinical Sensitivity - Sequencing with CNV PGxome

While the genetic causes of developmental delays are enormously diverse, some genetic causes of developmental disability are more common than others. An analysis of past results shows that the 99 genes on this panel account for more than 50% of positive developmental delay diagnoses at PreventionGenetics. Positive diagnosis indicates a likely pathogenic or pathogenic variant detected that fully explains a patient's phenotype. Additionally, this panel provides exome-wide CNV analysis, a chromosomal microarray (CMA) alternative, which can increase diagnostic yield, especially for patients who have not had a prior CMA. Considering past diagnostic rates, we expect this 99-gene panel to have a diagnostic yield of 10-15% for patients with developmental delay (for patients with prior microarray, or higher for those without).

This test will detect both large deletions and insertions (Copy Number Variants(CNVS)) as well as smaller sequence variants (nucleotide substitutions and small deletions and insertions (SNVs)) with high analytical sensitivity. Detection of trinucleotide repeat expansions (as seen in fragile X syndrome for example) requires an alternate test.

Indications for Test

This test is appropriate for any youth who is not meeting developmental milestones. The genetic causes of developmental delay are known to be enormously genetically diverse; therefore whole exome and genome sequencing should be considered as an alternative test.

Diseases

Name Inheritance OMIM ID
Alpha-Thalassemia Myelodysplasia Syndrome 300448
Alternating Hemiplegia of Childhood 2 AD 614820
Aml - Acute Myeloid Leukemia 601626
Angelman Syndrome AD 105830
Aniridia, Cerebellar Ataxia, And Mental Retardation AR 206700
ATR-X Syndrome XL 301040
Autism, Susceptibility to, 18 AD 615032
Autism, Susceptibility To, X-Linked 3 XL 300496
Bainbridge-Ropers Syndrome AD 615485
Baraitser-Winter Syndrome 1 AD 243310
Benign Familial Neonatal Seizures 1 AD 121200
Benign Familial Neonatal-Infantile Seizures AD 607745
Bosch-Boonstra-Schaaf optic atrophy syndrome AD 615722
CAPOS syndrome AD 601338
Cardio-Facio-Cutaneous Syndrome AD 115150
Charcot-Marie-Tooth Disease, Axonal, Type 2O AD 614228
CHARGE Association AD 214800
Chromosome 9Q Deletion Syndrome AD 610253
Coffin-Lowry Syndrome XL 303600
Coffin-Siris Syndrome 1 AD 135900
Coffin-Siris Syndrome 2 AD 614607
Coffin-Siris Syndrome 4 AD 614609
Cognitive Impairment With Or Without Cerebellar Ataxia AD 614306
Cohen Syndrome AR 216550
Congenital Contractures of the Limbs and Face, Hypotonia, and Developmental Delay AD 616266
Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder AD 617360
Corneal dystrophy, Fuchs endothelial, 3 AD 613267
Cornelia de Lange syndrome 2 XL 300590
Cornelia de Lange syndrome 5 XL 300882
Cowden Disease AD 158350
Desanto-Shinawi syndrome AD 616708
Developmental and Epileptic Encephalopathy 4 AD 612164
Dystonia 12 AD 128235
Dystonia 9 AD 601042
Encephalopathy, Neonatal Severe, Due To Mecp2 Mutations XL 300673
Epilepsy, Childhood Absence 5 612269
Epilepsy, Idiopathic Generalized, Suscpetibility to, 12 AD 614847
Epilepsy, Juvenile Myoclonic 5 611136
Epileptic encephalopathy, childhood-onset AD 615369
Epileptic Encephalopathy, Early Infantile, 11 AD 613721
Epileptic Encephalopathy, Early Infantile, 13 AD 614558
Epileptic Encephalopathy, Early Infantile, 17 AD 615473
Epileptic Encephalopathy, Early Infantile, 19 AD 615744
Epileptic Encephalopathy, Early Infantile, 2 XL 300672
Epileptic Encephalopathy, Early Infantile, 26 AD 616056
Epileptic Encephalopathy, Early Infantile, 27 AD 616139
Epileptic Encephalopathy, Early Infantile, 42 AD 617106
Epileptic Encephalopathy, Early Infantile, 43 AD 617113
Epileptic Encephalopathy, Early Infantile, 5 AD 613477
Epileptic Encephalopathy, Early Infantile, 54 AD 617391
Epileptic Encephalopathy, Early Infantile, 7 AD 613720
Episodic Ataxia Type 2 AD 108500
Exudative Vitreoretinopathy 7 AD 617572
Familial Colorectal Cancer 114500
Familial Hemiplegic Migraine Type 1 AD 141500
Familial Hemiplegic Migraine Type 3 AD 609634
Fg Syndrome XL 305450
FG Syndrome 4 300422
Focal Cortical Dysplasia Of Taylor 607341
Generalized Epilepsy With Febrile Seizures Plus, Type 2 AD 604403
Genitopatellar Syndrome AD 606170
Glass Syndrome AD 612313
Glioma Susceptibility 2 613028
Glut1 Deficiency Syndrome 1 AR 606777
Glut1 Deficiency Syndrome 2 AD 612126
Helsmoortel-van der Aa Syndrome AD 615873
Heyn-Sproul-Jackson syndrome 618724
Hypotonia, ataxia, and delayed development syndrome AD 617330
Hypotonia, Infantile, with Psychomotor Retardation and Characteristic Facies AR 615419
Intellectual developmental disorder with dysmorphic facies and ptosis AD 617333
Juvenile Myelomonocytic Leukemia 607785
Juvenile-Onset Dystonia AD 607371
Kabuki Syndrome 1 AD 147920
Kabuki Syndrome 2 XL 300867
Kallmann Syndrome 5 AD 612370
KBG Syndrome AD 148050
Koolen-De Vries Syndrome AD 610443
Lenz Microphthalmia Syndrome XL 309800
LEOPARD Syndrome AD 151100
LEOPARD Syndrome 3 AD 613707
Liver Cancer 114550
Lujan-Fryns Syndrome XL 309520
Lung Cancer 211980
Macrocephaly/Autism Syndrome AD 605309
Mandibulofacial dysostosis, Guion-Almeida type AD 610536
MECP2 Duplication Syndrome XL 300260
Medulloblastoma 155255
Meningioma, Familial 607174
Menke-Hennekam syndrome 1 618332
Menke-Hennekam syndrome 2 618333
Mental Retardation and Distinctive Facial Features with or without Cardiac Defects AD 616789
Mental Retardation And Microcephaly With Pontine And Cerebellar Hypoplasia XL 300749
Mental Retardation With Language Impairment And Autistic Features AD 613670
Mental Retardation, Autosomal Dominant 13; MRD13 AD 614563
Mental Retardation, Autosomal dominant 19 AD 615075
Mental Retardation, Autosomal Dominant 21 AD 615502
Mental Retardation, Autosomal Dominant 23 AD 615761
Mental Retardation, Autosomal Dominant 26 AD 615834
Mental Retardation, Autosomal Dominant 31 AD 616158
Mental retardation, autosomal dominant 32 AD 616268
Mental retardation, autosomal dominant 35 AD 616355
Mental Retardation, Autosomal Dominant 39 AD 616521
Mental retardation, autosomal dominant 40 AD 616579
Mental Retardation, Autosomal Dominant 41 AD 616944
Mental Retardation, Autosomal Dominant 44 AD 617061
Mental Retardation, Autosomal Dominant 5 AD 612621
Mental Retardation, Autosomal Dominant 52 AD 617796
Mental Retardation, Autosomal Dominant 6 AD 613970
Mental Retardation, Autosomal Dominant 7 AD 614104
Mental Retardation, Autosomal Dominant 9 AD 614255
Mental Retardation, Stereotypic Movements, Epilepsy, And/Or Cerebral Malformations AD 613443
Mental Retardation, X-Linked 1/78 XL 309530
Mental Retardation, X-Linked 102 XL 300958
Mental Retardation, X-Linked 19 XL 300844
Mental Retardation, X-linked 99 XL 300919
Mental retardation, X-linked 99, Syndromic, Female-Restricted XL 300968
Mental retardation, X-linked syndromic, Turner type XL 309590
Mental Retardation, X-Linked, Syndromic 13 XL 300055
Mental Retardation, X-Linked, Syndromic, Claes-Jensen Type XL 300534
Mental Retardation-Hypotonic Facies Syndrome X-Linked, 1 XL 309580
Metachondromatosis AD 156250
Mowat-Wilson Syndrome AD 235730
Myoclonic-Atonic Epilepsy AD 616421
Myoclonus, familial, 2 AD 618364
Neoplasm Of Ovary 167000
Neurodegeneration With Brain Iron Accumulation 5 XL 300894
Neurodevelopmental Disorder with Involuntary Movements AD 617493
Neurofibromatosis, Familial Spinal AD 162210
Neurofibromatosis, Type 1 AD 162200
Neurofibromatosis-Noonan Syndrome AD 601321
Neuropathy, Hereditary Sensory, Type IIC AR 614213
Nicolaides-Baraitser Syndrome AD 601358
Noonan Syndrome 1 AD 163950
Noonan Syndrome 7 AD 613706
Noonan Syndrome 8 AD 615355
Ogden Syndrome XL 300855
OHDO Syndrome, X-linked; OHDOX XL 300895
Phelan-Mcdermid Syndrome AD 606232
Pierpont syndrome AD 602342
Pilomatrixoma 132600
Pitt-Hopkins Syndrome AD 610954
Prostate Cancer 176807
Rett Syndrome XL 312750
Rett Syndrome, Congenital Variant AD 613454
Rhabdoid Tumor Predisposition Syndrome 2 AD 613325
Rubinstein-Taybi Syndrome AD 180849
Rubinstein-Taybi Syndrome 2 AD 613684
Schizophrenia 15 AD 613950
Schuurs-Hoeijmakers Syndrome AD 615009
Seizures, benign familial infantile, 5 AD 617080
Severe Myoclonic Epilepsy In Infancy AD 607208
Smith-Kingsmore Syndrome AD 616638
Smith-Lemli-Opitz Syndrome AR 270400
Smith-Magenis Syndrome AD 182290
Sotos' Syndrome AD 117550
Spastic Paraplegia 30 AR 610357
Spinal Muscular Atrophy, Lower Extremity, Autosomal Dominant; SMALED AD 158600
Spinocerebellar Ataxia 15 AD 606658
Spinocerebellar ataxia 29, congenital nonprogressive AD 117360
Spinocerebellar Ataxia 6 AD 183086
Stomatin-deficient cryohydrocytosis with neurologic defects AD 608885
Tatton-Brown-Rahman Syndrome AD 615879
Transposition Of Great Arteries AD 608808
Watson Syndrome AD 193520
White-Sutton Syndrome AD 616364
Wieacker-Wolff Syndrome XL 314580
Wiedemann-Steiner Syndrome AD 605130
X-LinkedMental Retardation With Cerebellar Hypoplasia And Distinctive Facial Appearance XL 300486
Xia-Gibbs syndrome AD 615829
Young Simpson Syndrome AD 603736

Related Tests

Name
PGxome®
Coffin-Siris Syndrome Panel
Kabuki Syndrome Panel

Citations

  • Bowling et al. 2017. PubMed ID: 28554332
  • ClinVar
  • DDD Study. 2015. PubMed ID: 25533962
  • Human Gene Mutation Database (Biobase).
  • Kaplanis et al. 2019. bioRxiv 797787
  • McRae et al. 2017. PubMed ID: 28135719
  • Wright et al. 2018. PubMed ID: 29323667
  • Zablotsky et al. 2019. PubMed ID: 31558576

Ordering/Specimens

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