X-linked Developmental Delay Panel

  • bpg-method PLUS
  • bpg-method SEQ
  • bpg-method DEL/DUP

Test code: NE0601

The Blueprint Genetics X-linked Developmental Delay Panel is a 94 gene test for genetic diagnostics of patients with clinical suspicion of X-linked developmental delay.

Developmental delay (also known as intellectual disability) is more common in males than females in the population, assumed to be due to mutations on the X chromosome. X-linked developmental delay accounts for approximately 16% of males with intellectual disability. In addition to a karyotype abnormalities and Fragile X syndrome caused by an expansion in FMR1, numerous X-linked genes exist where mutations have been described that result in either syndromic or non‐syndromic developmental delay. With this panel, the systematic screening of X-chromosomal nonsyndromic and syndromic developmental delay associated genes is feasible in a clinical setting.

About X-linked Developmental Delay

X-linked developmental delay refers to forms of intellectual disability, which are specifically associated with X-linked inheritance. As with most X-linked disorders, males are typically more heavily affected than females. Females with one affected X chromosome and one normal X chromosome tend to have milder symptoms. Several X-linked syndromes include intellectual disability as part of the presentation. These include Coffin-Lowry syndrome, MASA syndrome, X-linked alpha thalassemia mental retardation syndrome, Christianson syndrome and Lesch-Nyhan syndrome among others.

Availability

Results in 3-4 weeks. We do not offer a maternal cell contamination (MCC) test at the moment. We offer prenatal testing only for cases where the maternal cell contamination studies (MCC) are done by a local genetic laboratory. Read more: http://blueprintgenetics.com/faqs/#prenatal

Genes in the X-linked Developmental Delay Panel and their clinical significance
Gene Associated phenotypes Inheritance ClinVar HGMD
ABCD1* Adrenoleukodystrophy XL 58 654
ACSL4 Mental retardation XL 5 6
AFF2 Premature ovarian failure XL 3 23
AGTR2 Mental retardation XL 10
AP1S2 Mental retardation, syndromic, Fried (Pettigrew syndrome) XL 7 11
ARHGEF6 Mental retardation XL 1 4
ARHGEF9 Epileptic encephalopathy, early infantile XL 3 11
ARX Lissencephaly, Epileptic encephalopathy, Corpus callosum, agenesis of, with abnormal genitalia, Partington syndrome, Proud syndrome, Hydranencephaly with abnormal genitalia, Mental retardation XL 56 80
ATP6AP2 Mental retardation, syndromic, Hedera, Parkinsonism with spasticity XL 2 4
ATP7A Menkes disease XL 105 335
ATRX Carpenter-Waziri syndrome, Alpha-thalassemia/mental retardation syndrome, Holmes-Gang syndrome, Juberg-Marsidi syndrome, Smith-Fineman-Myers syndrome, Mental retardation-hypotonic facies syndrome XL 42 149
BCOR Microphthalmia, syndromic, Oculofaciocardiodental syndrome XL 22 44
BRWD3 Mental retardation XL 6 9
CASK Mental retardation and microcephaly with pontine and cerebellar hypoplasia, FG syndrome, Mental retardation XL 43 80
CDKL5 Epileptic encephalopathy, early infantile, Rett syndrome, atypical, Angelman-like syndrome XL 222 254
CUL4B Mental retardation, syndromic, Cabezas XL 9 34
DCX Lissencephaly, Subcortical laminal heterotopia XL 117 138
DKC1 Hoyeraal-Hreidarsson syndrome, Dyskeratosis congenita XL 45 69
DLG3 Mental retardation XL 8 13
ELK1* XL 2
FANCB Fanconi anemia XL 7 14
FGD1 Aarskog-Scott syndrome, Mental retardation, syndromic XL 18 42
FLNA Frontometaphyseal dysplasia, Osteodysplasty Melnick-Needles, Otopalatodigital syndrome type 1, Otopalatodigital syndrome type 2, Terminal osseous dysplasia with pigmentary defects XL 86 209
FMR1 Premature ovarian failure XL 11 78
FTSJ1 Mental retardation XL 5 9
GDI1 Mental retardation XL 4 8
GK* Glycerol kinase deficiency XL 8 34
GPC3 Simpson-Golabi-Behmel syndrome XL 22 65
GRIA3 Mental retardation XL 9 17
HCCS Linear skin defects with multiple congenital anomalies 1 (MIDAS syndrome) XL 6 13
HPRT1 Lesch-Nyhan syndrome, Kelley-Seegmiller syndrome XL 64 421
HSD17B10 17-beta-hydroxysteroid dehydrogenase X deficiency, Mental retardation, syndromic XL 8 12
HUWE1 Mental retardation, syndromic, Turner XL 8 31
IDS* Mucopolysaccharidosis XL 67 585
IGBP1 Corpus callosum, agenesis of, with mental retardation, ocular coloboma and micrognathia XL 1 1
IL1RAPL1 Mental retardation XL 11 37
IQSEC2 Mental retardation XL 16 36
KDM5C Mental retardation, syndromic, Claes-Jensen XL 21 44
KIAA2022 Mental retardation XL 19 11
KLF8 XL 1 2
L1CAM Mental retardation, aphasia, shuffling gait, and adducted thumbs (MASA) syndrome, Hydrocephalus due to congenital stenosis of aqueduct of Sylvius, Spastic, CRASH syndrome, Corpus callosum, partial agenesis XL 37 286
LAMP2 Danon disease XL 46 81
MAGT1 Immunodeficiency, with magnesium defect, Epstein-Barr virus infection and neoplasia XL 4 10
MAOA Brunner syndrome XL 5 15
MBTPS2 Keratosis follicularis spinulosa decalvans, IFAP syndrome, Palmoplantar keratoderma, mutilating, with periorificial keratotic plaques XL 8 24
MECP2 Angelman-like syndrome, Autism, Rett syndrome, Encephalopathy, Mental retardation XL 429 937
MED12 Ohdo syndrome, Mental retardation, with Marfanoid habitus, FG syndrome, Opitz-Kaveggia syndrome, Lujan-Fryns syndrome XL 17 19
MID1* Opitz GBBB syndrome XL 18 94
MTM1 Myopathy, centronuclear XL 152 284
NDP Exudative vitreoretinopathy, Norrie disease XL 25 155
NDUFA1 Mitochondrial complex I deficiency XL 3 5
NHS Nance-Horan syndrome, Cataract XL 19 43
NLGN3 Autism, Asperger syndrome XL 1 8
NLGN4X Autism, Asperger syndrome, Mental retardation XL 4 31
NSDHL Congenital hemidysplasia with ichthyosiform erythroderma and limb defects (CHILD syndrome), CK syndrome XL 15 28
NXF5* Familial heart block and focal segmental glomerulosclerosis XL 5
OCRL Lowe syndrome, Dent disease XL 33 251
OFD1 Simpson-Golabi-Behmel syndrome, Retinitis pigmentosa, Orofaciodigital syndrome, Joubert syndrome XL 129 148
OPHN1 Mental retardation, with cerebellar hypoplasia and distinctive facial appearance XL 13 34
OTC Ornithine transcarbamylase deficiency XL 326 503
PAK3 Mental retardation XL 6 8
PCDH19 Epileptic encephalopathy, early infantile XL 62 141
PDHA1 Leigh syndrome, Pyruvate dehydrogenase E1-alpha deficiency XL 39 165
PGK1 Phosphoglycerate kinase 1 deficiency XL 14 26
PHF6 Borjeson-Forssman-Lehmann syndrome XL 15 27
PHF8 Mental retardation syndrome, Siderius XL 10 8
PLP1 Spastic paraplegia, Pelizaeus-Merzbacher disease XL 41 266
PORCN Focal dermal hypoplasia XL 6 112
PQBP1 Renpenning syndrome XL 8 17
PRPS1* Deafness, Phosphoribosylpyrophosphate synthetase I superactivity, Arts syndrome XL 22 26
RAB39B Waisman parkinsonism-mental retardation syndrome, Mental retardation XL 4 11
RPL10 Autism XL 1 5
RPS6KA3 Coffin-Lowry syndrome, Mental retardation XL 35 161
SHROOM4 Stocco dos Santos mental retardation syndrome XL 3 9
SLC6A8* Creatine deficiency syndrome XL 19 127
SLC9A6 Mental retardation, syndromic, Christianson XL 21 18
SLC16A2 Allan-Herndon-Dudley syndrome XL 28 79
SMC1A Cornelia de Lange syndrome XL 39 54
SMS Mental retardation, Snyder-Robinson XL 9 10
SOX3 Panhypopituitarism XL 3 26
SRPX2 Rolandic epilepsy, mental retardation, and speech dyspraxia XL 1 3
SYN1 Epilepsy, with variable learning disabilities and behavior disorders XL 7 5
SYP Mental retardation XL 4 7
TIMM8A* Mohr-Tranebjaerg syndrome, Jensen syndrome, Opticoacoustic nerve atrophy with dementia XL 11 21
TSPAN7 Mental retardation XL 4 11
UBE2A Mental retardation, syndromic, Nascimento XL 4 21
UPF3B Mental retardation, syndromic XL 5 16
ZCCHC12 Intellectual disability XL 2
ZDHHC9 Mental retardation, syndromic, Raymond XL 4 10
ZDHHC15 Mental retardation XL 1
ZNF41 Mental retardation XL 4
ZNF81 Mental retardation XL 3 3
ZNF674 Mental retardation XL 6
ZNF711 Mental retardation XL 2 4

*Some regions of the gene are duplicated in the genome leading to limited sensitivity within the regions. Thus, low-quality variants are filtered out from the duplicated regions and only high-quality variants confirmed by other methods are reported out. Read more.

Gene, refers to HGNC approved gene symbol; Inheritance to inheritance patterns such as autosomal dominant (AD), autosomal recessive (AR) and X-linked (XL); ClinVar, refers to a number of variants in the gene classified as pathogenic or likely pathogenic in ClinVar (http://www.ncbi.nlm.nih.gov/clinvar/); HGMD, refers to a number of variants with possible disease association in the gene listed in Human Gene Mutation Database (HGMD, http://www.hgmd.cf.ac.uk/ac/). The list of associated (gene specific) phenotypes are generated from CDG (http://research.nhgri.nih.gov/CGD/) or Orphanet (http://www.orpha.net/) databases.

Gene Genomic location HG19 HGVS RefSeq RS-number Comment Reference
CDKL5 ChrX:18525053 c.-162-2A>G NM_003159.2 rs786204973
DKC1 ChrX:153991099 c.-142C>G NM_001363.3 rs199422241
L1CAM ChrX:153131293 c.2432-19A>C NM_000425.4
OCRL ChrX:128687279 c.239-4023A>G NM_000276.3
OFD1 ChrX:13773245 c.1130-22_1130-19delAATT NM_003611.2 rs312262865
OFD1 ChrX:13768358 c.935+706A>G NM_003611.2 rs730880283
PDHA1 ChrX:19377861 c.*79_*90dupAGTCAATGAAAT NM_001173454.1
TIMM8A ChrX:100601671 c.133-23A>C NM_004085.3 rs869320666

The strengths of this test include:

  • Blueprint Genetics is one of the few laboratories worldwide with CAP and ISO-15189 accreditation for NGS panels and CLIA certification
  • Superior sequencing quality
  • Careful selection of genes based on current literature, our experience and the most current mutation databases
  • Transparent and easy access to quality and performance data at the patient level that are accessible via our Nucleus portal
  • Transparent and reproducible analytical validation for each panel (see Test performance section; for complete details, see our Analytic Validation)
  • Sequencing and high resolution del/dup analysis available in one test
  • Inclusion of non-coding disease causing variants where clinically indicated (please see individual Panel descriptions)
  • Interpretation of variants following ACMG variant classification guidelines
  • Comprehensive clinical statement co-written by a PhD geneticist and a clinician specialist

 

This test does not detect the following:

  • Complex inversions
  • Gene conversions
  • Balanced translocations
  • Mitochondrial DNA variants
  • Variants in regulatory or non-coding regions of the gene unless otherwise indicated (please see Non-coding disease causing variants covered by the panel). This mean for instance intronic variants locating deeper than 15 nucleotides from the exon-intron boundary.

 

This test may not reliably detect the following:

  • Low level mosaicism
  • Stretches of mononucleotide repeats
  • Indels larger than 50bp
  • Single exon deletions or duplications
  • Variants within pseudogene regions/duplicated segments
  • Disorders caused by long repetitive sequences (e.g. trinucleotide repeat expansions)

 

The sensitivity of this test may be reduced if DNA is extracted by a laboratory other than Blueprint Genetics.

For additional information, please refer to the Test performance section and see our Analytic Validation.

Blueprint Genetics offers a comprehensive X-linked Developmental Delay Panel that covers classical genes associated with x-linked mental retardation. The genes are carefully selected based on the existing scientific evidence, our experience and most current mutation databases. Candidate genes are excluded from this first-line diagnostic test. The test does not recognise balanced translocations or complex inversions, and it may not detect low-level mosaicism. The test should not be used for analysis of sequence repeats or for diagnosis of disorders caused by mutations in the mitochondrial DNA.

Analytical validation is a continuous process at Blueprint Genetics. Our mission is to improve the quality of the sequencing process and each modification is followed by our standardized validation process. Average sensitivity and specificity in Blueprint NGS Panels is 99.3% and 99.9% for detecting SNPs. Sensitivity to for indels vary depending on the size of the alteration: 1-10bps (96.0%), 11-20 bps (88.4%) and 21-30 bps (66.7%). The longest detected indel was 46 bps by sequence analysis. Detection limit for Del/Dup (CNV) analysis varies through the genome depending on exon size, sequencing coverage and sequence content. The sensitivity is 71.5% for single exon deletions and duplications and 99% for three exons’ deletions and duplications. We have validated the assays for different starting materials including EDTA-blood, isolated DNA (no FFPE) and saliva that all provide high-quality results. The diagnostic yield varies substantially depending on the used assay, referring healthcare professional, hospital and country. Blueprint Genetics’ Plus Analysis (Seq+Del/Dup) maximizes the chance to find molecular genetic diagnosis for your patient although Sequence Analysis or Del/Dup Analysis may be cost-effective first line test if your patient’s phenotype is suggestive for a specific mutation profile.

The sequencing data generated in our laboratory is analyzed with our proprietary data analysis and annotation pipeline, integrating state-of-the art algorithms and industry-standard software solutions. Incorporation of rigorous quality control steps throughout the workflow of the pipeline ensures the consistency, validity and accuracy of results. The highest relevance in the reported variants is achieved through elimination of false positive findings based on variability data for thousands of publicly available human reference sequences and validation against our in-house curated mutation database as well as the most current and relevant human mutation databases. Reference databases currently used are the 1000 Genomes Project (http://www.1000genomes.org), the NHLBI GO Exome Sequencing Project (ESP; http://evs.gs.washington.edu/EVS), the Exome Aggregation Consortium (ExAC; http://exac.broadinstitute.org), ClinVar database of genotype-phenotype associations (http://www.ncbi.nlm.nih.gov/clinvar) and the Human Gene Mutation Database (http://www.hgmd.cf.ac.uk). The consequence of variants in coding and splice regions are estimated using the following in silico variant prediction tools: SIFT (http://sift.jcvi.org), Polyphen (http://genetics.bwh.harvard.edu/pph2/), and Mutation Taster (http://www.mutationtaster.org).

Through our online ordering and statement reporting system, Nucleus, the customer can access specific details of the analysis of the patient. This includes coverage and quality specifications and other relevant information on the analysis. This represents our mission to build fully transparent diagnostics where the customer gains easy access to crucial details of the analysis process.

In addition to our cutting-edge patented sequencing technology and proprietary bioinformatics pipeline, we also provide the customers with the best-informed clinical report on the market. Clinical interpretation requires fundamental clinical and genetic understanding. At Blueprint Genetics our geneticists and clinicians, who together evaluate the results from the sequence analysis pipeline in the context of phenotype information provided in the requisition form, prepare the clinical statement. Our goal is to provide clinically meaningful statements that are understandable for all medical professionals, even without training in genetics.

Variants reported in the statement are always classified using the Blueprint Genetics Variant Classification Scheme modified from the ACMG guidelines (Richards et al. 2015), which has been developed by evaluating existing literature, databases and with thousands of clinical cases analyzed in our laboratory. Variant classification forms the corner stone of clinical interpretation and following patient management decisions. Our statement also includes allele frequencies in reference populations and in silico predictions. We also provide PubMed IDs to the articles or submission numbers to public databases that have been used in the interpretation of the detected variants. In our conclusion, we summarize all the existing information and provide our rationale for the classification of the variant.

A final component of the analysis is the Sanger confirmation of the variants classified as likely pathogenic or pathogenic. This does not only bring confidence to the results obtained by our NGS solution but establishes the mutation specific test for family members. Sanger sequencing is also used occasionally with other variants reported in the statement. In the case of variant of uncertain significance (VUS) we do not recommend risk stratification based on the genetic finding. Furthermore, in the case VUS we do not recommend use of genetic information in patient management or genetic counseling. For some cases Blueprint Genetics offers a special free of charge service to investigate the role of identified VUS.

We constantly follow genetic literature adapting new relevant information and findings to our diagnostics. Relevant novel discoveries can be rapidly translated and adopted into our diagnostics without delay. These processes ensure that our diagnostic panels and clinical statements remain the most up-to-date on the market.

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ICD & CPT codes

CPT codes

SEQ 81470
DEL/DUP 81471

Accepted sample types

  • EDTA blood, min. 1 ml
  • Purified DNA, min. 5μg
  • Saliva (Oragene DNA OG-500 kit)

Label the sample tube with your patient’s name, date of birth and the date of sample collection.

Note that we do not accept DNA samples isolated from formalin-fixed paraffin-embedded (FFPE) tissue.

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