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X-Linked Intellectual Disability Sequencing Panel with CNV Detection

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
Order Kits
TEST METHODS

Sequencing with CNV

Test Code Test Copy GenesCPT Code Copy CPT Codes
2675 ABCD1 81405,81479 Add to Order
ACSL4 81479,81479
AFF2 81479,81479
AGTR2 81479,81479
AIFM1 81479,81479
ALG13 81479,81479
AP1S2 81479,81479
ARHGEF6 81479,81479
ARHGEF9 81479,81479
ARSE 81479,81479
ARSF 81479,81479
ARX 81404,81403
ATP6AP2 81479,81479
ATRX 81479,81479
BCAP31 81479,81479
BCOR 81479,81479
BCORL1 81479,81479
BRWD3 81479,81479
CASK 81479,81479
CCDC22 81479,81479
CDK16 81479,81479
CDKL5 81406,81405
CLCN4 81479,81479
CLIC2 81479,81479
CNKSR2 81479,81479
CUL4B 81479,81479
DCX 81405,81479
DDX3X 81479,81479
DKC1 81479,81479
DLG3 81479,81479
DRP2 81479,81479
EBP 81479,81479
EIF2S3 81479,81479
FAAH2 81479,81479
FGD1 81479,81479
FLNA 81479,81479
FMR1 81479,81479
FRMPD4 81479,81479
FTSJ1 81406,81405
GDI1 81479,81479
GK 81479,81479
GPC3 81479,81479
GRIA3 81479,81479
H2BFWT 81479,81479
HCFC1 81479,81479
HDAC8 81479,81479
HMGB3 81479,81479
HNRNPH2 81479,81479
HPRT1 81479,81479
HSD17B10 81479,81479
HUWE1 81479,81479
IDS 81405,81479
IGBP1 81479,81479
IL1RAPL1 81479,81479
IQSEC2 81479,81479
KCNE5 81479,81479
KDM5C 81407,81479
KDM6A 81479,81479
KIF4A 81479,81479
KLHL15 81479,81479
L1CAM 81407,81479
LAMP2 81405,81479
LAS1L 81479,81479
MAGEA11 81479,81479
MAOA 81479,81479
MAP7D3 81479,81479
MBTPS2 81479,81479
MECP2 81302,81304
MED12 81479,81479
MID1 81479,81479
MID2 81479,81479
MSL3 81479,81479
NAA10 81479,81479
NDP 81404,81403
NEXMIF 81479,81479
NHS 81479,81479
NLGN3 81405,81479
NLGN4X 81405,81404
NONO 81479,81479
NSDHL 81479,81479
OPHN1 81479,81479
OTC 81405,81479
PAK3 81479,81479
PCDH19 81405,81479
PDHA1 81406,81405
PGK1 81479,81479
PHF6 81479,81479
PHF8 81479,81479
PIGA 81479,81479
PLP1 81405,81404
POLA1 81479,81479
PQBP1 81405,81404
PRPS1 81479,81479
PTCHD1 81479,81479
RAB39B 81479,81479
RBM10 81479,81479
RLIM 81479,81479
RNF113A 81479,81479
RPL10 81479,81479
RPS6KA3 81479,81479
SHROOM4 81479,81479
SLC16A2 81405,81404
SLC35A2 81479,81479
SLC6A8 81479,81479
SLC7A3 81479,81479
SLC9A6 81406,81479
SMC1A 81479,81479
SMS 81479,81479
SOX3 81479,81479
SRPX2 81479,81479
SSR4 81479,81479
SYN1 81479,81479
SYP 81479,81479
SYTL5 81479,81479
TAF1 81479,81479
THOC2 81479,81479
TMLHE 81479,81479
TSPAN7 81479,81479
UBE2A 81479,81479
UPF3B 81479,81479
USP27X 81479,81479
USP9X 81479,81479
WDR45 81479,81479
ZC4H2 81479,81479
ZCCHC12 81479,81479
ZDHHC9 81479,81479
ZMYM3 81479,81479
ZNF711 81479,81479
Full Panel Price* $1310
Test Code Test Copy Genes Total Price CPT Codes Copy CPT Codes
2675 Genes x (128) $1310 81302, 81304, 81403(x2), 81404(x6), 81405(x14), 81406(x4), 81407(x2), 81479(x226) Add to Order
Pricing Comments

CPT codes 81470 and 81471 can be used if at least 60 of the genes in the panel are analyzed. 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.

Targeted Testing

For ordering sequencing of targeted known variants, please proceed to our Targeted Variants landing page.

Turnaround Time

The great majority of tests are completed within 26 days.

Clinical Sensitivity

Genetic causes of intellectual disability (ID) have been detected in 25–60% of the cases, and pathogenic copy number variants (CNVs) have a diagnostic yield of ~10-15% (McLaren and Bryson. 1987. PubMed ID: 3322329; Kaufman et al. 2010. PubMed ID: 21124998; Fieremans et al. 2016. PubMed ID: 27159028). However, CMA analysis is limited in its ability to identify low-level mosaicism and balanced translocations (Miller et al. 2010. PubMed ID: 20466091) and up to ~3% of pathogenic variants are estimated to be located within non-coding regions of the genome (Vissers et al. 2016. PubMed ID: 26503795; Chiurazzi and Pirozzi. 2016. PubMed ID: 27127621). Approximately 5-10% of cases of intellectual disability in males are due to CNVs on the X chromosome (Madrigal et al. 2007. PubMed ID: 18047645). Based on previously published reports of large XLID patient cohorts, we estimate this panel to identify pathogenic variants in 20-40% of Fragile X negative XLID cases (de Brouwer et al. 2007. PubMed ID: 17221867; Hu et al. 2016. PubMed ID: 25644381), with increased success rates in scenarios where clinically recognizable features are also observed.

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Clinical Features

Intellectual Disability (ID) (also referred to as mental retardation) is a group of genetically heterogeneous disorders characterized by substantial impairment in cognitive abilities, communication, self-direction, and social and behavioral adaptive skills (American Association of Intellectual and Developmental Disabilities, AAIDD). Intelligence is assessed across three domains designated as conceptual, social, and practical ability (Diagnostic and Statistical Manual of Mental Disorder (DSM-5)). ID is not a single entity, but rather a general symptom of neurologic dysfunction diagnosed before 18 years of age in 1–3% of the population, irrespective of any social class and culture (Vissers et al. 2016. PubMed ID: 26503795; Kaufman et al. 2010. PubMed ID: 21124998).

X-linked Intellectual Disability (XLID) accounts for 5-10% of ID cases in males (Lubs et al. 2012. PubMed ID: 22482801; Tzschach. 2015. PubMed ID: 25649377). XLID can be divided into syndromic forms (which are characterized by XLID accompanied by malformations, dysmorphic features, or neurological abnormalities) and non-syndromic forms (which are characterized by XLID without any additional features). Non-syndromic ID is more common and accounts for the majority of XLIDs (de Brouwer et al. 2007. PubMed ID: 17221867), with 80% of the reported causative genes on the X chromosome (Kaufman et al. 2010. PubMed ID: 21124998).

Genetics

Although non-genetic factors (infection, trauma) can result in cognitive impairment, most severe forms of ID have a genetic basis. A genetic etiology is reported to account for as many as 60% of cases (McLaren and Bryson. 1987. PubMed ID: 3322329; Kaufman et al. 2010. PubMed ID: 21124998; Fieremans et al. 2016. PubMed ID: 27159028). Pathogenic variants occurring at scales of resolution ranging from large cytogenetic abnormalities to single nucleotide variants and even epigenetic alterations are associated with ID (Topper et al. 2011. PubMed ID: 21627642). A large number of studies have pointed out the association of chromosomal abnormalities (Trisomy 21, Fragile X syndrome, translocations, recurrent microdeletions/duplications of autosomes, etc.) and pathogenic copy number variations (CNV) with ID cases (Ropers and Hamel. 2005. PubMed ID: 15630421; Rauch et al. 2006. PubMed ID: 16917849, Zahir and Friedman. 2007. PubMed ID: 17850622). Chromosomal abnormalities and CNVs can explain ~15% and ~10% of ID cases, respectively. The fragile X mental retardation 1 (FMR1) gene remains the most commonly mutated gene in ID (~0.5% of ID cases, 25% of XLID cases) and is the most common single gene defect in XLID (Basel-Vanagaite. 2008. PubMed ID: 19070297; Tzschach. 2015. PubMed ID: 25649377).

XLIDs are heterogeneous disorders. Nearly all affected individuals are males, but skewed X-inactivation in females carrying pathogenic variants on the X chromosome can also impact disease severity (Plenge et al. 2002. PubMed ID: 12068376; Fieremans et al. 2016. PubMed ID: 27159028). Compared to the autosomes, there is an enrichment of genes on the X chromosome with established roles in the central nervous system and cognitive function (Hu et al. 2016. PubMed ID: 25644381; de Brouwer et al. 2007. PubMed ID: 17221867; Nguyen and Disteche. 2006. PubMed ID: 16341221). This panel focuses on genes associated with an established monogenic form of XLID (Renieri et al. 2005. PubMed ID: 15690397; de Brouwer et al. 2007. PubMed ID: 17221867; Tarpey et al. 2009. PubMed ID: 19377476; Piton et al. 2013. PubMed ID: 23871722; Hu et al. 2016. PubMed ID: 25644381). A wide variety of causative variants (missense, nonsense, splicing, small deletions and insertions) have been reported. Except for a few genes, most genes in this panel have also been reported to have large deletions/duplications and complex genomic rearrangements (Mignon-Ravix et al. 2014. PubMed ID: 24817631; Human Gene Mutation Database).

Gene Disorder
ABCD1 Adrenoleukodystrophy, XL
ACSL4 Mental retardation, X-linked 63
AFF2 Mental retardation, X-linked, fragile site, folic acid sensitive type
AGTR2 Intellectual disability, XL
AIFM1 Cowchock syndrome, XL
ALG13 Congenital disorder of glycosylation, type Is, XL
AP1S2 Mental retardation, X-linked syndromic 5, XL
ARHGEF6 Mental retardation, X-linked 46
ARHGEF9 Intellectual disability associated with epileptic encephalopathy, early infantile, XL
ARSE Chondrodysplasia punctata, X-linked
ARSF Intellectual disability
ARX Mental retardation, X-linked syndromic and non-syndromic, XL
ATP6AP2 Mental retardation, X-linked
ATRX Alpha-thalassemia/mental retardation syndrome, XL
BCAP31 Deafness, dystonia, and cerebral hypomyelination, XL
BCOR Oculofaciocardiodental syndrome, XL
BCORL1 Intellectual disability, XL
BRWD3 Mental retardation, X-linked 93
CASK FG syndrome 4, XL
CCDC22 Ritscher-Schinzel syndrome 2, XL
CDK16 Intellectual disability, XL
CDKL5 Epileptic encephalopathy, early infantile, 2, XL
CLCN4 Intellectual disability, XL
CLIC2 Intellectual disability, XL
CNKSR2 X-linked intellectual disability and seizures, non-syndromic
CUL4B Mental retardation, X-linked, syndromic 15 (Cabezas type)
DCX Lissencephaly, X-linked
DDX3X Mental retardation, X-linked 102
DKC1 Dyskeratosis congenita, X-linked
DLG3 Mental retardation, X-linked 90
DRP2 Intellecutual disability, Autism spectrum disorder, Schizophrenia susceptibility
EBP MEND syndrome/Chondrodysplasia punctata, X-linked
EIF2S3 MEHMO syndrome
FAAH2 Intellectual disability, XL
FGD1 Aarskog-Scott syndrome
FLNA Heterotopia, periventricular, XL
FMR1 Fragile X syndrome
FRMPD4 Mental retardation, X-linked 104
FTSJ1 Mental retardation, X-linked 9
GDI1 Mental retardation, X-linked 41
GK Glycerol kinase deficency
GPC3 Simpson-Golabi-Behmel syndrome, type 1
GRIA3 Mental retardation, X-linked 94
H2BFWT Developmental Delay
HCFC1 Mental retardation, X-linked 3 (methylmalonic acidemia and homocysteinemia, cblX type )
HDAC8 Cornelia de Lange syndrome 5
HMGB3 Microphthalmia, syndromic 13
HNRNPH2 Mental retardation, X-linked, Bain type
HPRT1 Lesch-Nyhan syndrome
HSD17B10 Mental retardation, X-linked
HUWE1 Mental retardation, X-linked, non-syndromic
IDS Mucopolysaccharidosis II, XL
IGBP1 Corpus callosum, agenesis of, with mental retardation, ocular coloboma and micrognathia
IL1RAPL1 Mental retardation, X-linked 21/34
IQSEC2 Mental retardation, X-linked 1, syndromic or non-syndromic
KCNE5 Alport syndrome, midface hypoplasia, and elliptocytosis
KDM5C Mental retardation, X-linked, syndromic, Claes-Jensen type
KDM6A Kabuki syndrome 2
KIF4A Mental retardation, X-linked 100
KLHL15 Mental retardation, X-linked 103
L1CAM MASA syndrome, XL
LAMP2 Danon disease, XL
LAS1L Wilson-Turner syndrome
MAGEA11 Intellectual disability
MAOA Brunner syndrome, XL
MAP7D3 Intellectual disability, XL
MBTPS2 IFAP syndrome with or without BRESHECK syndrome, XL
MECP2 Rett syndrome, XL
MED12 Lujan-Fryns syndrome, Opitz-Kaveggia syndrome, XL
MID1 Opitz G/BBB syndrome, type I, XL
MID2 Mental retardation, X-linked 101
MSL3 Intellectual disability
NAA10 Intellectual disability with long QT, XL
NDP Norrie disease, XL
NEXMIF Mental retardation, X-linked 98
NHS Nance-Horan syndrome, XL
NLGN3 Autism susceptibility, X-linked 1/Asperger syndrome susceptibility, X-linked 1
NLGN4X Mental retardation, X-linked
NONO Mentalretardation, X-linked, syndromic 34
NSDHL CK syndrome, XL
OPHN1 Mental retardation, X-linked, with cerebellar hypoplasia and distinctive facial appearance
OTC Ornithine transcarbamylase deficiency, XL
PAK3 Mental retardation, X-linked 30/47
PCDH19 Epileptic encephalopathy, early infantile, 9 XL
PDHA1 Pyruvate dehydrogenase E1-alpha deficiency, XL
PGK1 Phosphoglycerate kinase 1 deficiency, XL
PHF6 Borjeson-Forssman-Lehmann syndrome, XL
PHF8 Mental retardation syndrome, X-linked, Siderius type
PIGA Multiple congenital anomalies-hypotonia-seizures syndrome 2
PLP1 Pelizaeus-Merzbacher disease, XL
POLA1 Pigmentary disorder, reticulate, with systemic manifestations, X-linked
PQBP1 Renpenning syndrome, XL
PRPS1 Arts syndrome, XL
PTCHD1 Intellectual disability, Autism, susceptibility to, X-linked 4
RAB39B Mental retardation, X-linked 72, Waisman syndrome, early onset Parkinson disease, XL
RBM10 Intellectual disability, XL
RLIM Mental retardation, X-linked 61
RNF113A Trichothiodystrophy 5, nonphotosensitive
RPL10 Intellectual disability XL
RPS6KA3 Coffin-Lowry syndrome, XL
SHROOM4 Stocco dos Santos X-linked mental retardation syndrome
SLC16A2 Allan-Herndon-Dudley syndrome, XL
SLC35A2 Congenital disorders of glycosylation, type Iim
SLC6A8 Cerebral creatine deficiency syndrome 1
SLC7A3 Intellectual disability, XL
SLC9A6 Mental retardation, X-linked syndromic, Christianson type
SMC1A Intellectual disability, XL
SMS Mental retardation, X-linked, Snyder-Robinson type
SOX3 Mental retardation, X-linked, with isolated growth hormone deficiency
SRPX2 Rolandic epilepsy, mental retardation, and speech dyspraxia
SSR4 Congenital disorders of glycosylation, type Iy
SYN1 Epilepsy, X-linked, with variable learning disabilities and behavior disorders
SYP Mental retardation, X-linked 96
SYTL5 Intellectual disability
TAF1 Mental retardation, X-linked, syndromic 33
THOC2 Mental retardation, X-linked 12/35
TMLHE Autism, susceptibility to, X-linked 6
TSPAN7 Mental retardation, X-linked 58
UBE2A Mental retardation, X-linked syndromic, Nascimento-type
UPF3B Mental retardation, X-linked, syndromic 14
USP27X Mental retardation, X-linked 105
USP9X Mental retardation, X-linked 99
WDR45 Neurodegeneration with brain iron accumulation 5, XL
ZC4H2 Wieacker-Wolff syndrome, XL
ZCCHC12 Intellectual disability, XL
ZDHHC9 Mental retardation, X-linked syndromic, Raymond type
ZMYM3 Intellectual disability, XL
ZNF711 Mental retardation, X-linked 97
Testing Strategy

For this Next Generation Sequencing (NGS) test, sequencing is accomplished by capturing specific regions with an optimized solution-based hybridization kit, followed by massively parallel sequencing of the captured DNA fragments.

For Sanger sequencing, polymerase chain reaction (PCR) is used to amplify targeted regions. After purification of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit. PCR products are resolved by electrophoresis on an ABI 3730xl capillary sequencer. In nearly all cases, cycle sequencing is performed separately in both the forward and reverse directions.

Copy number variants (CNVs) are also detected from NGS data. We utilize a CNV calling algorithm that compares mean read depth and distribution for each target in the test sample against multiple matched controls. Neighboring target read depth and distribution and zygosity of any variants within each target region are used to reinforce CNV calls. All CNVs are confirmed using another technology such as aCGH, MLPA, or PCR before they are reported.

This panel typically provides ≥98% 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.

Genes without complete coverage: TMLHE (NM_018196.3, exons 8 and 9).

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

Indications for Test

This panel is recommended for patients with syndromic or nonsyndromic suspected X-linked intellectual disability who have had negative fragile X repeat expansion testing. Prenatal diagnosis is possible depending if the genetic diagnosis has been firmly established in an affected family member.

Genes

Official Gene Symbol OMIM ID
ABCD1 300371
ACSL4 300157
AFF2 300806
AGTR2 300034
AIFM1 300169
ALG13 300776
AP1S2 300629
ARHGEF6 300267
ARHGEF9 300429
ARSE 300180
ARSF 300003
ARX 300382
ATP6AP2 300556
ATRX 300032
BCAP31 300398
BCOR 300485
BCORL1 300688
BRWD3 300553
CASK 300172
CCDC22 300859
CDK16 311550
CDKL5 300203
CLCN4 302910
CLIC2 300138
CNKSR2 300724
CUL4B 300304
DCX 300121
DDX3X 300160
DKC1 300126
DLG3 300189
DRP2 300052
EBP 300205
EIF2S3 300161
FAAH2 300654
FGD1 300546
FLNA 300017
FMR1 309550
FRMPD4 300838
FTSJ1 300499
GDI1 300104
GK 300474
GPC3 300037
GRIA3 305915
H2BFWT 300507
HCFC1 300019
HDAC8 300269
HMGB3 300193
HNRNPH2 300610
HPRT1 308000
HSD17B10 300256
HUWE1 300697
IDS 300823
IGBP1 300139
IL1RAPL1 300206
IQSEC2 300522
KCNE5 300328
KDM5C 314690
KDM6A 300128
KIF4A 300521
KLHL15 300980
L1CAM 308840
LAMP2 309060
LAS1L 300964
MAGEA11 300344
MAOA 309850
MAP7D3 300930
MBTPS2 300294
MECP2 300005
MED12 300188
MID1 300552
MID2 300204
MSL3 300609
NAA10 300013
NDP 300658
NEXMIF 300524
NHS 300457
NLGN3 300336
NLGN4X 300427
NONO 300084
NSDHL 300275
OPHN1 300127
OTC 300461
PAK3 300142
PCDH19 300460
PDHA1 300502
PGK1 311800
PHF6 300414
PHF8 300560
PIGA 311770
PLP1 300401
POLA1 312040
PQBP1 300463
PRPS1 311850
PTCHD1 300828
RAB39B 300774
RBM10 300080
RLIM 300379
RNF113A 300951
RPL10 312173
RPS6KA3 300075
SHROOM4 300579
SLC16A2 300095
SLC35A2 314375
SLC6A8 300036
SLC7A3 300443
SLC9A6 300231
SMC1A 300040
SMS 300105
SOX3 313430
SRPX2 300642
SSR4 300090
SYN1 313440
SYP 313475
SYTL5 0
TAF1 313650
THOC2 300395
TMLHE 300777
TSPAN7 300096
UBE2A 312180
UPF3B 300298
USP27X 300975
USP9X 300072
WDR45 300526
ZC4H2 300897
ZCCHC12 300701
ZDHHC9 300646
ZMYM3 300061
ZNF711 314990
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Diseases

Name Inheritance OMIM ID
Aarskog Syndrome XL 305400
Adrenoleukodystrophy XL 300100
Allan-Herndon-Dudley Syndrome XL 300523
Arts Syndrome XL 301835
Asperger Syndrome, X-Linked, Susceptibility To, 1 XL 300494
ATR-X Syndrome XL 301040
Autism, Susceptibility To, X-Linked 1 XL 300425
Autism, Susceptibility To, X-Linked 2 XL 300495
Autism, Susceptibility to, X-linked 4 XL 300830
Autism, Susceptibility To, X-Linked 5 XL 300847
Autism, Susceptibility to, X-linked 6 XL 300872
Borjeson-Forssman-Lehmann Syndrome XL 301900
Cerebral Creatine Deficiency Syndrome 1 XL 300352
Chondrodysplasia Punctata 1, X-Linked Recessive XL 302950
CK syndrome XL 300831
Coffin-Lowry Syndrome XL 303600
Congenital Disorder of Glycosylation Type IIm XL 300896
Congenital Disorder of Glycosylation Type Iy XL 300934
Cornelia de Lange syndrome 2 XL 300590
Cornelia de Lange syndrome 5 XL 300882
Corpus Callosum, Agenesis Of, With Mental Retardation, Ocular Coloboma, And Micrognathia XL 300472
Cowchock Syndrome XL 310490
Danon Disease XL 300257
Deafness, Dystonia, and Cerebral Hypomyelination XL 300475
Dyskeratosis Congenita X-Linked XL 305000
Epilepsy, X-Linked, With Variable Learning Disabilities And Behavior Disorders XL 300491
Epileptic Encephalopathy, Early Infantile, 2 XL 300672
Epileptic Encephalopathy, Early Infantile, 36 XL 300884
Epileptic Encephalopathy, Early Infantile, 8 XL 300607
Epileptic Encephalopathy, Early Infantile, 9 XL 300088
Fragile X Syndrome XL 300624
Glycerol Kinase Deficiency XL 307030
Ichthyosis Follicularis Atrichia Photophobia Syndrome XL 308205
Kabuki Syndrome 2 XL 300867
Lesch-Lyhan Syndrome XL 300322
Lujan-Fryns Syndrome XL 309520
MEHMO Syndrome XL 300148
MEND Syndrome XL 300960
Mental Retardation 105 XL 300984
Mental Retardation, with or without Nystagmus XL 300422
Mental Retardation, X-Linked 1/78 XL 309530
Mental Retardation, X-linked 100 XL 300923
Mental Retardation, X-linked 101 XL 300928
Mental Retardation, X-Linked 102 XL 300958
Mental Retardation, X-linked 103 XL 300982
Mental Retardation, X-linked 104 XL 300983
Mental Retardation, X-linked 12/35 XL 300957
Mental Retardation, X-Linked 21 XL 300143
Mental Retardation, X-Linked 3 (Methylmalonic Acidemia and Homocysteinemia, cblX Type) XL 309541
Mental Retardation, X-Linked 30 XL 300558
Mental Retardation, X-Linked 41 XL 300849
Mental Retardation, X-Linked 46 XL 300436
Mental Retardation, X-Linked 58 XL 300210
Mental Retardation, X-linked 61 XL 300978
Mental Retardation, X-Linked 63 XL 300387
Mental Retardation, X-Linked 72 XL 300271
Mental Retardation, X-Linked 9 XL 309549
Mental Retardation, X-Linked 90 XL 300850
Mental Retardation, X-Linked 93 XL 300659
Mental Retardation, X-Linked 96 XL 300802
Mental Retardation, X-Linked 97 XL 300803
Mental Retardation, X-linked 98 XL 300912
Mental Retardation, X-linked 99 XL 300919
Mental retardation, X-linked 99, Syndromic, Female-Restricted XL 300968
Mental Retardation, X-linked, FRAXE Type XL 309548
Mental Retardation, X-Linked, Syndromic 10 XL 300220
Mental Retardation, X-Linked, Syndromic 14 XL 300676
Mental Retardation, X-linked, Syndromic 32 XL 300886
Mental Retardation, X-linked, Syndromic 33 XL 300966
Mental Retardation, X-linked, Syndromic 34 XL 300967
Mental Retardation, X-linked, Syndromic, Bain Type XL 300986
Mental Retardation, X-Linked, Syndromic, Christianson Type XL 300243
Mental Retardation, X-Linked, Syndromic, Claes-Jensen Type XL 300534
Mental Retardation, X-Linked, Syndromic, Hedera Type XL 300423
Mental Retardation, X-Linked, Syndromic, Nascimento Type XL 300860
Mental Retardation, X-Linked, Syndromic, Raymond Type XL 300799
Mental Retardation, X-Linked, Syndromic, Turner Type XL 300706
Mental Retardation, X-Linked, Syndromic, Wu Type XL 300699
Mental Retardation, X-Linked, With Panhypopituitarism XL 300123
Mental Retardation, X-Linked, With Short Stature, Hypogonadism, And Abnormal Gait XL 300354
Microphthalmia, Syndromic 13 XL 300915
Monoamine Oxidase A Deficiency XL 300615
Mucopolysaccharidosis, MPS-II XL 309900
Multiple Congenital Anomalies-Hypotonia-Seizures Syndrome 2 XL 300868
Nance-Horan Syndrome XL 302350
Neurodegeneration With Brain Iron Accumulation 5 XL 300894
Norrie Disease XL 310600
Oculofaciocardiodental Syndrome XL 300166
Ogden Syndrome XL 300855
Opitz G/BBB Syndrome, Type I XL 300000
Ornithine Carbamoyltransferase Deficiency XL 311250
Pelizaeus-Merzbacher Disease XL 312080
Pettigrew Syndrome XL 304340
Phosphoglycerate Kinase 1 Deficiency XL 300653
Pigmentary Disorder, Reticulate, with Systemic Manifestations, X-linked XL 301220
Pyruvate Dehydrogenase E1-Alpha Deficiency XL 312170
Renpenning Syndrome 1 XL 309500
Rett Syndrome XL 312750
Ritscher-Schinzel Syndrome 2 XL 300963
Rolandic Epilepsy, Mental Retardation, And Speech Dyspraxia, X-Linked XL 300643
Siderius X-Linked Mental Retardation Syndrome XL 300263
Simpson-Golabi-Behmel Syndrome XL 312870
Snyder Robinson Syndrome XL 309583
Spastic Paraplegia 1 XL 303350
Stocco Dos Santos Syndrome XL 300434
TARP Syndrome XL 311900
Trichothiodystrophy 5, nonphotosensitive XL 300953
Wieacker-Wolff Syndrome XL 314580
Wilson-Turner syndrome XL 309585
X-Linked Lissencephaly XL 300067
X-Linked Lissencephaly 2 XL 300215
X-Linked Periventricular Heterotopia XL 300049
X-LinkedMental Retardation With Cerebellar Hypoplasia And Distinctive Facial Appearance XL 300486

Related Test

Name
PGxome®

CONTACTS

Genetic Counselors
Geneticist
Citations
  • Basel-Vanagaite. 2008. PubMed ID: 19070297
  • Chiurazzi and Pirozzi. 2016. PubMed ID: 27127621
  • de Brouwer et al. 2007. PubMed ID: 17221867
  • Fieremans et al. 2016. PubMed ID: 27159028
  • Hu et al. 2016. PubMed ID: 25644381
  • Human Gene Mutation Database (Bio-base).
  • Kaufman et al. 2010. PubMed ID: 21124998
  • Lubs et al. 2012. PubMed ID: 22482801
  • Madrigal et al. 2007. PubMed ID: 18047645
  • McLaren and Bryson. 1987. PubMed ID: 3322329
  • Mignon-Ravix et al. 2014. PubMed ID: 24817631
  • Miller et al. 2010. PubMed ID: 20466091
  • Nguyen and Disteche. 2006. PubMed ID: 16341221
  • Piton et al. 2013. PubMed ID: 23871722
  • Plenge et al. 2002. PubMed ID: 12068376
  • Rauch et al. 2006. PubMed ID: 16917849
  • Renieri et al. 2005. PubMed ID: 15690397
  • Ropers and Hamel. 2005. PubMed ID: 15630421
  • Tarpey et al. 2009. PubMed ID: 19377476
  • Topper et al. 2011. PubMed ID: 21627642
  • Tzschach et al. 2015. PubMed ID: 25649377
  • Vissers et al. 2016. PubMed ID: 26503795
  • Zahir and Friedman. 2007. PubMed ID: 17850622
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TEST METHODS

Exome Sequencing with CNV Detection

Test Procedure

For PGxome® we use Next Generation Sequencing (NGS) technologies to cover the coding regions of targeted genes plus 10 bases of flanking non-coding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. As required, genomic DNA is extracted from patient specimens. Patient DNA corresponding to these regions is captured using Agilent Clinical Research Exome hybridization probes. Captured DNA is sequenced on the NovaSeq 6000 using 2x150 bp paired-end reads (Illumina, San Diego, CA, USA). The following quality control metrics are generally achieved: >97% of target bases are covered at >20x, and mean coverage of target bases >120x. Data analysis and interpretation is performed by the internally developed software Titanium-Exome. In brief, the output data from the NovaSeq 6000 is converted to fastqs by Illumina Bcl2Fastq, and mapped by BWA. Variant calls are made by the GATK Haplotype caller and annotated using in house software and SnpEff. Variants are filtered and annotated using VarSeq (www.goldenhelix.com).

For Sanger sequencing, polymerase chain reaction (PCR) is used to amplify targeted regions. After purification of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit. PCR products are resolved by electrophoresis on an ABI 3730xl capillary sequencer. In nearly all cases, cycle sequencing is performed separately in both the forward and reverse directions.

Copy number variants (CNVs) are also detected from NGS data. We utilize a CNV calling algorithm that compares mean read depth and distribution for each target in the test sample against multiple matched controls. Neighboring target read depth and distribution and zygosity of any variants within each target region are used to reinforce CNV calls. All CNVs are confirmed using another technology such as aCGH, MLPA, or PCR before they are reported.

Analytical Validity

NextGen Sequencing: As of March 2016, 6.36 Mb of sequence (83 genes, 1557 exons) generated in our lab was compared between Sanger and NextGen methodologies. We detected no differences between the two methods. The comparison involved 6400 total sequence variants (differences from the reference sequences). Of these, 6144 were nucleotide substitutions and 256 were insertions or deletions. About 65% of the variants were heterozygous and 35% homozygous. The insertions and deletions ranged in length from 1 to over 100 nucleotides.

In silico validation of insertions and deletions in 20 replicates of 5 genes was also performed. The validation included insertions and deletions of lengths between 1 and 100 nucleotides. Insertions tested in silico: 2200 between 1 and 5 nucleotides, 625 between 6 and 10 nucleotides, 29 between 11 and 20 nucleotides, 25 between 21 and 49 nucleotides, and 23 at or greater than 50 nucleotides, with the largest at 98 nucleotides. All insertions were detected. Deletions tested in silico: 1813 between 1 and 5 nucleotides, 97 between 6 and 10 nucleotides, 32 between 11 and 20 nucleotides, 20 between 21 and 49 nucleotides, and 39 at or greater than 50 nucleotides, with the largest at 96 nucleotides. All deletions less than 50 nucleotides in length were detected, 13 greater than 50 nucleotides in length were missed. Our standard NextGen sequence variant calling algorithms are generally not capable of detecting insertions (duplications) or heterozygous deletions greater than 100 nucleotides. Large homozygous deletions appear to be detectable.

Copy Number Variant Analysis: The PGxome test detects most larger deletions and duplications including intragenic CNVs and large cytogenetic events; however aberrations in a small percentage of regions may not be accurately detected due to sequence paralogy (e.g., pseudogenes, segmental duplications), sequence properties, deletion/duplication size (e.g., 1-3 exons vs. 4 or more exons), and inadequate coverage. In general, sensitivity for single, double, or triple exon CNVs is ~70% and for CNVs of four exon size or larger is >95%, but may vary from gene-to-gene based on exon size, depth of coverage, and characteristics of the region.

Analytical Limitations

Interpretation of the test results is limited by the information that is currently available. Better interpretation should be possible in the future as more data and knowledge about human genetics and this specific disorder are accumulated.

When sequencing does not reveal any heterozygous differences from the reference sequence, we cannot be certain that we were able to detect both patient alleles.

For technical reasons, the PGxome test is not 100% sensitive. Some exons cannot be efficiently captured, and some genes cannot be accurately sequenced because of the presence of multiple copies in the genome. Therefore, a small fraction of sequence variants will not be detected.

We sequence coding exons for all available transcripts plus 10 bp of flanking non-coding DNA for each exon. We also sequence other regions within or near genes in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere.  Unless specifically indicated, test reports contain no information about other portions of genes.

In most cases, we are unable to determine the phase of sequence variants. In particular, when we find two likely causative mutations for recessive disorders, we cannot be certain that the mutations are on different alleles.

Our ability to detect minor sequence variants due to somatic mosaicism is limited. Sequence variants that are present in less than 50% of the patient's nucleated cells may not be detected.

Runs of mononucleotide repeats (eg (A)n or (T)n) with n >8 in the reference sequence are generally not analyzed because of strand slippage during amplification.

Unless otherwise indicated, DNA sequence data is obtained from a specific cell-type (usually leukocytes if taken from whole blood). Test reports contain no information about the DNA sequence in other cell-types.

We cannot be certain that the reference sequences are correct.

Balanced translocations or inversions are only rarely detected.

Certain types of sex chromosome aneuploidy may not be detected.  

Our ability to detect CNVs due to somatic mosaicism is limited.

We have confidence in our ability to track a specimen once it has been received by PreventionGenetics. However, we take no responsibility for any specimen labeling errors that occur before the sample arrives at PreventionGenetics.

A negative finding does not rule out a genetic diagnosis.

Genetic counseling to help to explain test results to the patients and to discuss reproductive options is recommended.

Order Kits

Ordering Options


myPrevent - Online Ordering
  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
REQUISITION FORM
  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

SPECIMEN TYPES
WHOLE BLOOD

(Delivery accepted Monday - Saturday)

  • Collect 3 ml -5 ml (5 ml preferred) of whole blood in EDTA (purple top tube) or ACD (yellow top tube). For Test #500-DNA Banking only, collect 10 ml -20 ml of whole blood.
  • For small babies, we require a minimum of 1 ml of blood.
  • Only one blood tube is required for multiple tests.
  • Ship blood tubes at room temperature in an insulated container. Do not freeze blood.
  • During hot weather, include a frozen ice pack in the shipping container. Place a paper towel or other thin material between the ice pack and the blood tube.
  • In cold weather, include an unfrozen ice pack in the shipping container as insulation.
  • At room temperature, blood specimen is stable for up to 48 hours.
  • If refrigerated, blood specimen is stable for up to one week.
  • Label the tube with the patient name, date of birth and/or ID number.

DNA

(Delivery accepted Monday - Saturday)

  • Send in screw cap tube at least 5 µg -10 µg of purified DNA at a concentration of at least 20 µg/ml for NGS and Sanger tests and at least 5 µg of purified DNA at a concentration of at least 100 µg/ml for gene-centric aCGH, MLPA, and CMA tests, minimum 2 µg for limited specimens.
  • For requests requiring more than one test, send an additional 5 µg DNA per test ordered when possible.
  • DNA may be shipped at room temperature.
  • Label the tube with the composition of the solute, DNA concentration as well as the patient’s name, date of birth, and/or ID number.
  • We only accept genomic DNA for testing. We do NOT accept products of whole genome amplification reactions or other amplification reactions.

CELL CULTURE

(Delivery preferred Monday - Thursday)

  • PreventionGenetics should be notified in advance of arrival of a cell culture.
  • Culture and send at least two T25 flasks of confluent cells.
  • Some panels may require additional flasks (dependent on size of genes, amount of Sanger sequencing required, etc.). Multiple test requests may also require additional flasks. Please contact us for details.
  • Send specimens in insulated, shatterproof container overnight.
  • Cell cultures may be shipped at room temperature or refrigerated.
  • Label the flasks with the patient name, date of birth, and/or ID number.
  • We strongly recommend maintaining a local back-up culture. We do not culture cells.
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