OVERVIEW

DEFINE

Global developmental delay and intellectual disability (GDD/ID) affect up to 3% of children <5 years old and is defined as a delay in ≥2 developmental domains*. Up to 40% of GDD/ID cases are caused by genetic factors and can occur in isolation or accompanied by other symptoms including malformations and neurological disorders. Children with GDD/ID exhibit mixed and diverse symptoms, and up to two-thirds do not have a single group of symptoms that can point towards a specific diagnosis. As a result, many patients undergo a long diagnostic journey before necessary genetic tests are performed to define the cause of GDD/ID.

Our tests combine chromosomal analyses and (comprehensive) gene panels associated with many different disorders with overlapping features, providing a diagnostic solution for children with GDD/ID.

DECIDE

Having a diagnosis can help you decide on a management plan or treatment options for your child. Our genetic counselling offers information regarding the diagnosis, identifies associated medical risks, and provides a long-term prognosis, thereby improving your child’s clinical outcome and may help prevent further complications.

*Developmental domains include physical, cognitive, speech/language, social and emotional

IMPORTANCE OF GETTING TESTED

Children with a GDD/ID disorder often require lifelong support, which can have a profound effect on their lives and that of their family. A timely diagnosis is crucial for therapeutic intervention and the best outcome for your child. Identifying the cause can provide a prognosis, refine treatment options, evaluate recurrence risks and provide closure to the diagnostic journey. In turn, this can improve your mental health and that of your child, while validating your concerns and empowering you to advocate for your child.

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Children <5 years with a
significant delay in
≥2 developmental domains*

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Children with an
autism spectrum disorder

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Children with dysmorphic features

POSSIBLE OUTCOMES OF THE TEST

A molecular genetic diagnostic report outlining the results of the sequencing analysis is provided. Changes in DNA sequences (variants) can be detrimental and lead to the development of a cardiac or aortic disorder, including asymptomatic disorders that develop later in life. We will report pathogenic and likely pathogenic variants as well as variants of unknown significance.
Pathogenic and likely pathogenic variants mean the genetic cause of the observed symptoms has been identified and may help determine the right treatment and management plan.
Variants of unknown significance means there was not enough evidence to classify the variant as either pathogenic or neutral. Annual variant reclassification and testing family members is recommended.
It is important to note that a negative result does not guarantee the absence of a disorder or that the disorder does not have a genetic cause. Genetic testing is an evolving field and may not detect all variants or there may not currently be enough evidence to classify all variants that lead to an inherited disease.

MEDICAL GENETIC COUNSELLING

We provide expert medical genetic counselling as part of a genetic testing journey. Genetic counselling is a process of communication that supports patients and their relatives before and after genetic testing. It is educational, impartial and nondirective. Prior to any genetic test, genetic counsellors will obtain a detailed family history, explain the method of testing that will be used, its risks and benefits, the limitations of the diagnosis and the implications of making a genetic diagnosis (Elliott and Friedman, 2018, Nat Rev Genet 19:735).

Upon receiving the genetic test results, genetic counselling can help the specialist physician and the patient to interpret them. They can be advised of the consequences of the results including the probability of developing the genetic disorder or passing it on to children, as well as ways to prevent, avoid or reduce these risks (Yang and Kim, 2018, Ann Lab Med 38:291). Our goal of counselling is to provide the patient with greater knowledge and thus, a better understanding of the results and the ability to make a more informed decision.

OUR TESTS

FRAGILE X

Fragile X syndrome is the most common monogenic inherited cause of intellectual disability. Males are more frequently affected than females, and generally with greater severity.

CHROMOSOMAL ANALYSIS

Karyotyping: detection of gross genetic changes involving several megabases including aneuploidies

Microarray CGH: screening of deletions and duplications

GENE PANELS

• Autism Spectrum • Brain Malformations (Comprehensive, Lissencephaly, Pontocerebellar Hypoplasia, Tubulinopathies) • Coffin-Siris • Congenital Disorders Of Glycosylation • Cornelia De Lange • GPI Anchor Deficiency • Intellectual Disability • Macrocephaly • Microcephaly • Overgrowth • Pediatric Neurotransmitter • RASopathies, Comprehensive • Rett • Rett And Related Disorders

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ACCEPTED MATERIAL

1 ml EDTA Blood

TURNAROUND TIME

15-25 working days

TECHNOLOGY

DNA is isolated and next generation sequencing is performed on all coding exons and conserved intronic regions. Single base pair changes, small deletions and duplications and copy number variants (CNV) are identified. Sequencing runs result in a Quality Score of >30 (accuracy >99.9%) in at least 75% of all bases with a coverage of >20-fold. CNV detection sensitivity is 76.99% and precision is 62.59% (with GC limitation between 0.4 and 0.6 per target sensitivity is 77.04% and precision is 84.10%). Variant classification is performed following ACMG guidelines (Richards et al. 2015, Genet Med 17:405; Kearney et al. 2011, Genet Med 13:680).

Test Methodology
Sequencing

Next generation
sequencing (Illumina)

Enrichment

Twist Human Core
Exome plus Ref Seq
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SNV and CNV data anlaysis

Illumina DRAGEN
Bio-IT Platform

Data Evaluation

VarSeq by
GoldenHelix

Reference Genome

hg38, NCBI GR38

Quality Criteria

>30 (precision >99,9%)
in min. 75% of bases

SNV detection sensitivity

99.92-99.93%; confirmation of reported SNV with Sanger
sequencing, data analysis with
SeqPilot

Classification of variants

Richards et al. 2015, Genet Med
17:405; Ellard et al. “ACGS Best
Practice Guidelines for Variant
Classification 2020″

in silico algorithms

MaxEntScan,
SpliceSiteFinder-like,
REVEL

Databases

HGMD Professional
release, ClinVar,
gnomAD

OUR TESTS

Genes: ALDH5A1, AP1S2, ARX, ATRX, AUTS2, BRAF, CACNA1C, CASK, CDKL5, CHD7, CHD8, CNOT3, CNTNAP2, DHCR7, DPP6, EHMT1, FGD1, FOXG1, FOXP1, FOXP2, GNAI1, GRIN2B, HPRT1, KDM5C, L1CAM, MBD5, MECP2, MED12, MEF2C, MID1, NHS, NIPBL, NLGN3, NLGN4X, NRXN1, NSD1, OPHN1, PCDH19, PHF6, PNKP, PQBP1, PTCHD1, PTEN, PTPN11, RAB39B, RAI1, RPL10, SCN1A, SHANK2, SHANK3, SLC9A6, SMARCB1, SMC1A, SMC3, TBR1, TCF4, TMLHE, TSC1, TSC2, UBE2A, UBE3A, VPS13B, ZEB2

Genes: AHI1, ARFGEF2, ARX, CASK, CC2D2A, CEP290, CEP41, DCX, EOMES, FKRP, FKTN, FLNA, GPR56, KIF7, LAMC3, LARGE, MKS1, NDE1, NPHP1, OCLN, OPHN1, PAFAH1B1, POMGNT1, POMT1, POMT2, PQBP1, RARS2, RELN, RPGRIP1L, SRPX2, TMEM138, TMEM216, TMEM237, TMEM67, TSEN2, TSEN34, TSEN54, TUBA1A, TUBA8, TUBB2B, TUBB3, VLDLR, VRK1

Genes: ARX, DCX, KATNB1, MACF1, NDE1, PAFAH1B1, RELN, TMTC3, TUBA1A

Genes: AMPD2, CHMP1A, CLP1, COASY, EXOSC3, EXOSC8, EXOSC9, PCLO, RARS2, SEPSECS, SLC25A46, TBC1D23, TOE1, TSEN15, TSEN2, TSEN34, TSEN54, VPS53, VRK1

Genes: TBCD, TUBA1A, TUBA8, TUBB, TUBB2A, TUBB2B, TUBB3, TUBG1

Genes: ARID1A, ARID1B, ARID2, DPF2, SMARCA4, SMARCB1, SMARCC2, SMARCE1, SOX11, SOX4

Genes: ALG1, ALG11, ALG12, ALG13, ALG2, ALG3, ALG6, ALG8, ALG9, B4GALT1, CAD, CCDC115, COG1, COG4, COG5, COG6, COG7, COG8, DDOST, DOLK, DPAGT1, DPM1, DPM2, DPM3, MGAT2, MOGS, MPDU1, MPI, NGLY1, PGM1, PMM2, RFT1, SLC35A1, SLC35A2, SLC35C1, SLC39A8, SRD5A3, SSR4, STT3A, STT3B, TMEM165, TMEM199, TUSC3

Genes: ANKRD11, BRD4, HDAC8, NIPBL, RAD21, SMC1A, SMC3

Genes: microarray CGH (aCGH)

Genes: FMR1

Genes: GPAA1, PGAP1, PGAP2, PGAP3, PIGA, PIGB, PIGC, PIGG, PIGH, PIGL, PIGM, PIGN, PIGO, PIGP, PIGQ, PIGS, PIGT, PIGU, PIGV, PIGW, PIGY

Genes: ABCD1, ACSL4, AFF2, AGTR2, AIFM1, ALG13, AMER1, AP1S2, AP4B1, AP4E1, AP4M1, AP4S1, ARHGEF6, ARHGEF9, ARX, ATP6AP2, ATP7A, ATRX, BCAP31, BCOR, BRWD3, CA8, CASK, CC2D1A, CCDC22, CDH15, CDKL5, CLCN4, CLIC2, CNKSR2, CNTNAP2, CRBN, CREBBP, CUL4B, DCX, DDX3X, DKC1, DLG3, DMD, EBP, EIF2S3, EP300, ERLIN2, FAAH2, FANCB, FGD1, FLNA, FMR1, FOXG1, FOXP1, FRMPD4, FTSJ1, GDI1, GJB1, GK, GPC3, GPKOW, GRIA3, GRIK2, GRIN2B, GSPT2, HCCS, HCFC1, HDAC6, HDAC8, HMGB3, HNRNPH2, HPRT1, HSD17B10, HUWE1, IDS, IGBP1, IKBKG, IL1RAPL1, IQSEC2, KDM5C, KDM6A, KIAA2022, KIF4A, KIRREL3, KLF8, KLHL15, L1CAM, LAMP2, LAS1L, MAGT1, MAN1B1, MAOA, MBTPS2, MECP2, MED12, MEF2C, MID1, MID2, MSL3, MTM1, NAA10, NDP, NDUFA1, NEXMIF, NHS, NLGN3, NLGN4X, NONO, NRXN1, NSDHL, NXF5, OCRL, OFD1, OGT, OPHN1, OTC, PAK3, PCDH19, PDHA1, PGK1, PHF6, PHF8, PIGA, PLP1, PORCN, PQBP1, PRPS1, PRSS12, PTCHD1, RAB39B, RAB40AL, RAI1, RBM10, RBMX, RLIM, RNF113A, RPL10, RPS6KA3, SHROOM4, SLC16A2, SLC25A5, SLC6A8, SLC9A6, SMC1A, SMS, SOBP, SOX3, SRPX2, SSR4, ST3GAL3, STAG2, STXBP1, SYN1, SYNGAP1, SYP, TAF1, TCF4, THOC2, TIMM8A, TMLHE, TRAPPC9, TSPAN7, TUSC3, UBE2A, UBE3A, UPF3B, USP27X, USP9X, VLDLR, WDR13, WDR45, ZC3H14, ZC4H2, ZCCHC12, ZDHHC15, ZDHHC9, ZEB2, ZMYM3, ZNF41, ZNF526, ZNF674, ZNF711, ZNF81

Genes: ABCC9, AKT3, AMER1, ASPA, BRWD3, CCDC22, CCND2, CDKN1C, CHD8, CUL4B, DIS3L2, DNMT3A, DVL1, DVL3, EZH2, FOXP1, GCDH, GFAP, GLI3, GPC3, GRIA3, HEPACAM, HERC1, HRAS, HUWE1, KIF7, KPTN, KRAS, LZTR1, MED12, MLC1, MTOR, NDUFA1, NFIB, NFIX, NONO, NRAS, NSD1, NXN, OFD1, PIGA, PIGN, PIGT, PIGV, PIK3R2, PPP1CB, PPP2R5D, PTCH1, PTCH2, PTEN, RAB39B, RAF1, RHEB, RIT1, RNF135, ROR2, SETD2, SHOC2, SOS1, SUFU, TBC1D7, TMCO1, UPF3B, WASHC5, WNT5A, ZDHHC9

Genes: ANKLE2, ASPM, CDK5RAP2, CDK6, CENPE, CENPF, CENPJ, CEP135, CEP152, CIT, COPB2, DONSON, KDM6A, KIF14, KMT2D, KNL1, MCPH1, MFSD2A, NCAPD2, NCAPD3, NCAPH, NUP37, PCNT, PHC1, SASS6, STIL, WDFY3, WDR62, ZEB1, ZNF335

Genes: CDKN1C, DIS3L2, DNMT3A, EED, EZH2, GPC3, HERC1, HIST1H1E, NFIX, NSD1, OFD1

Genes: DBH, DDC, DNAJC12, GCH1, MAOA, PCBD1, PTS, QDPR, SLC18A2, SLC6A3, SPR, TH, TPH1, TPH2

Genes: BRAF, CBL, HRAS, KRAS, LZTR1, MAP2K1, MAP2K2, MRAS, NF1, NRAS, PPP1CB, PTPN11, RAF1, RASA2, RIT1, RRAS, SHOC2, SOS1, SOS2, SPRED1

Genes: CDKL5, FOXG1, MECP2

OUR NETWORK