X-linked Developmental Delay Panel

SEQmethod-seq-icon Our Sequence Analysis is based on a proprietary targeted sequencing method OS-Seq™ and offers panels targeted for genes associated with certain phenotypes. A standard way to analyze NGS data for finding the genetic cause for Mendelian disorders. Results in 21 days. DEL/DUPmethod-dup-icon Targeted Del/Dup (CNV) analysis is used to detect bigger disease causing deletions or duplications from the disease-associated genes. Results in 21 days. PLUSmethod-plus-icon Plus Analysis combines Sequence + Del/Dup (CNV) Analysis providing increased diagnostic yield in certain clinical conditions, where the underlying genetic defect may be detectable by either of the analysis methods. Results in 21 days.

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.

Genes in the X-linked Developmental Delay Panel and their clinical significance
GeneAssociated phenotypesInheritanceClinVarHGMD
ABCD1*AdrenoleukodystrophyXL58654
ACSL4Mental retardationXL56
AFF2Premature ovarian failureXL323
AGTR2Mental retardationXL10
AP1S2Mental retardation, syndromic, Fried (Pettigrew syndrome)XL711
ARHGEF6Mental retardationXL14
ARHGEF9Epileptic encephalopathy, early infantileXL311
ARXLissencephaly, Epileptic encephalopathy, Corpus callosum, agenesis of, with abnormal genitalia, Partington syndrome, Proud syndrome, Hydranencephaly with abnormal genitalia, Mental retardationXL5680
ATP6AP2Mental retardation, syndromic, Hedera, Parkinsonism with spasticityXL24
ATP7AMenkes diseaseXL105335
ATRXCarpenter-Waziri syndrome, Alpha-thalassemia/mental retardation syndrome, Holmes-Gang syndrome, Juberg-Marsidi syndrome, Smith-Fineman-Myers syndrome, Mental retardation-hypotonic facies syndromeXL42149
BCORMicrophthalmia, syndromic, Oculofaciocardiodental syndromeXL2244
BRWD3Mental retardationXL69
CASKMental retardation and microcephaly with pontine and cerebellar hypoplasia, FG syndrome, Mental retardationXL4380
CDKL5Epileptic encephalopathy, early infantile, Rett syndrome, atypical, Angelman-like syndromeXL222254
CUL4BMental retardation, syndromic, CabezasXL934
DCXLissencephaly, Subcortical laminal heterotopiaXL117138
DKC1Hoyeraal-Hreidarsson syndrome, Dyskeratosis congenitaXL4569
DLG3Mental retardationXL813
ELK1*XL2
FANCBFanconi anemiaXL714
FGD1Aarskog-Scott syndrome, Mental retardation, syndromicXL1842
FLNAFrontometaphyseal dysplasia, Osteodysplasty Melnick-Needles, Otopalatodigital syndrome type 1, Otopalatodigital syndrome type 2, Terminal osseous dysplasia with pigmentary defectsXL86209
FMR1Premature ovarian failureXL1178
FTSJ1Mental retardationXL59
GDI1Mental retardationXL48
GK*Glycerol kinase deficiencyXL834
GPC3Simpson-Golabi-Behmel syndromeXL2265
GRIA3Mental retardationXL917
HCCSLinear skin defects with multiple congenital anomalies 1 (MIDAS syndrome)XL613
HPRT1Lesch-Nyhan syndrome, Kelley-Seegmiller syndromeXL64421
HSD17B1017-beta-hydroxysteroid dehydrogenase X deficiency, Mental retardation, syndromicXL812
HUWE1Mental retardation, syndromic, TurnerXL831
IDS*MucopolysaccharidosisXL67585
IGBP1Corpus callosum, agenesis of, with mental retardation, ocular coloboma and micrognathiaXL11
IL1RAPL1Mental retardationXL1137
IQSEC2Mental retardationXL1636
KDM5CMental retardation, syndromic, Claes-JensenXL2144
KIAA2022Mental retardationXL1911
KLF8XL12
L1CAMMental retardation, aphasia, shuffling gait, and adducted thumbs (MASA) syndrome, Hydrocephalus due to congenital stenosis of aqueduct of Sylvius, Spastic, CRASH syndrome, Corpus callosum, partial agenesisXL37286
LAMP2Danon diseaseXL4681
MAGT1Immunodeficiency, with magnesium defect, Epstein-Barr virus infection and neoplasiaXL410
MAOABrunner syndromeXL515
MBTPS2Keratosis follicularis spinulosa decalvans, IFAP syndrome, Palmoplantar keratoderma, mutilating, with periorificial keratotic plaquesXL824
MECP2Angelman-like syndrome, Autism, Rett syndrome, Encephalopathy, Mental retardationXL429937
MED12Ohdo syndrome, Mental retardation, with Marfanoid habitus, FG syndrome, Opitz-Kaveggia syndrome, Lujan-Fryns syndromeXL1719
MID1*Opitz GBBB syndromeXL1894
MTM1Myopathy, centronuclearXL152284
NDPExudative vitreoretinopathy, Norrie diseaseXL25155
NDUFA1Mitochondrial complex I deficiencyXL35
NHSNance-Horan syndrome, CataractXL1943
NLGN3Autism, Asperger syndromeXL18
NLGN4XAutism, Asperger syndrome, Mental retardationXL431
NSDHLCongenital hemidysplasia with ichthyosiform erythroderma and limb defects (CHILD syndrome), CK syndromeXL1528
NXF5*Familial heart block and focal segmental glomerulosclerosisXL5
OCRLLowe syndrome, Dent diseaseXL33251
OFD1Simpson-Golabi-Behmel syndrome, Retinitis pigmentosa, Orofaciodigital syndrome, Joubert syndromeXL129148
OPHN1Mental retardation, with cerebellar hypoplasia and distinctive facial appearanceXL1334
OTCOrnithine transcarbamylase deficiencyXL326503
PAK3Mental retardationXL68
PCDH19Epileptic encephalopathy, early infantileXL62141
PDHA1Leigh syndrome, Pyruvate dehydrogenase E1-alpha deficiencyXL39165
PGK1Phosphoglycerate kinase 1 deficiencyXL1426
PHF6Borjeson-Forssman-Lehmann syndromeXL1527
PHF8Mental retardation syndrome, SideriusXL108
PLP1Spastic paraplegia, Pelizaeus-Merzbacher diseaseXL41266
PORCNFocal dermal hypoplasiaXL6112
PQBP1Renpenning syndromeXL817
PRPS1*Deafness, Phosphoribosylpyrophosphate synthetase I superactivity, Arts syndromeXL2226
RAB39BWaisman parkinsonism-mental retardation syndrome, Mental retardationXL411
RPL10AutismXL15
RPS6KA3Coffin-Lowry syndrome, Mental retardationXL35161
SHROOM4Stocco dos Santos mental retardation syndromeXL39
SLC6A8*Creatine deficiency syndromeXL19127
SLC9A6Mental retardation, syndromic, ChristiansonXL2118
SLC16A2Allan-Herndon-Dudley syndromeXL2879
SMC1ACornelia de Lange syndromeXL3954
SMSMental retardation, Snyder-RobinsonXL910
SOX3PanhypopituitarismXL326
SRPX2Rolandic epilepsy, mental retardation, and speech dyspraxiaXL13
SYN1Epilepsy, with variable learning disabilities and behavior disordersXL75
SYPMental retardationXL47
TIMM8A*Mohr-Tranebjaerg syndrome, Jensen syndrome, Opticoacoustic nerve atrophy with dementiaXL1121
TSPAN7Mental retardationXL411
UBE2AMental retardation, syndromic, NascimentoXL421
UPF3BMental retardation, syndromicXL516
ZCCHC12Intellectual disabilityXL2
ZDHHC9Mental retardation, syndromic, RaymondXL410
ZDHHC15Mental retardationXL1
ZNF41Mental retardationXL4
ZNF81Mental retardationXL33
ZNF674Mental retardationXL6
ZNF711Mental retardationXL24
  • * 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.

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

SEQ81470
DEL/DUP81471

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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