Molecular Genetics X-Linked Intellectual Disabilities Sequencing and Deletion/Duplication Panel

Syndromic and non-syndromic intellectual disability associated with genes on the X chromosome account for approximately 5% of intellectual disability (ID) in males; prevalence of X-linked ID is approximately 1/600-1000 for males (Lubs et al. 2012AJHG 90; Gecz et al. 2009 Trends Genet 25).  Most cases are non-syndromic, with few other features to aid in diagnosis.  Thus, screening large sets of genes on the X chromosome for sequence-level mutations provides a rapid and cost-effective method to detect changes in genes that can contribute to X-linked intellectual disability, particularly when family history suggests an X-linked inheritance pattern.  The current panel comprises 88 genes on the X chromosome that have been associated with ID. Further, in concert with exon-level deletion and duplication analysis, the current testing modality can provide a comprehensive genomics solution for X-linked ID in both males and females.

Reasons for Referral:

• Negative Fragile X testing (in males) and negative chromosomal microarray testing*
• Unexplained intellectual disability
• Familial intellectual disability with inheritance patterns suggestive of X-linked transmission

*Tests for Fragile X and for submicroscopic regional copy number gains and losses (chromosomal microarray) are available in our laboratory and may require additional specimen.  It is recommended that these tests be performed before the sequencing and del/dup panel.   Please contact our lab for more information.

This test has two components:

Component 1: Next generation sequencing will analyze the exons or coding regions of 88 X-linked Intellectual Disability genes using Illumina NextSeq 500 technology and preparing samples using hybridization probes to enrich exonic regions.  Any gaps in coverage in clinically validated genes are completed with traditional Sanger sequencing such that 100% of the coding region of the above genes are covered at 10x coverage or more.  Promoter, intronic, etc. regions are not assessed here but may contain variants that impact gene function.

Component 2: Microarray Analysis – A customized CytoSure “exon-centric” array (Oxford Gene Technology) will be used to detect deletions and duplications. The targeted array has enhanced probes targeted to the exonic regions of the 88 X-linked Intellectual Disability genes medically relevant genes. The arrays will be run using Agilent SureScan technology. This array is an ideal complement to the next generation sequencing approach to provide a comprehensive mutation spectrum analysis for X-linked Intellectual Disability.

X-Linked Intellectual Disabilities Panel (88 genes): ACSL4, AFF2, AP1S2, ARHGEF9, ARX, ATP6AP2, ATP7A, ATRX, BCOR, BRWD3, CASK, CCDC22, CDKL5, CLIC2, CNKSR2, CUL4B, DCX, DKC1, DLG3, DMD, FANCB, FGD1, FLNA, FMR1, FRMPD4, FTSJ1, GDI1, GK, GPC3, GRIA3, HCCS, HPRT1, HSD17B10, HUWE1, IDS, IGBP1, IL1RAPL1, IQSEC2, KDM5C, KIAA2022, L1CAM, LAMP2, MAOA, MBTPS2, MECP2, MED12, MID1, NAA10, NDP, NDUFA1, NHS, NLGN3, NLGN4X, NSDHL, OCRL, OFD1, OPHN1, OTC, PAK3, PCDH19, PDHA1, PGK1, PHF6, PHF8, PLP1, PORCN, PQBP1, PRPS1, PTCHD1, RAB39B, RBM10, RPL10, RPS6KA3, SHROOM4, SLC16A2, SLC9A6, SMC1A, SMS, SOX3, SYN1, SYP, TIMM8A, TSPAN7, UBE2A, UPF3B, ZDHHC15, ZDHHC9, ZNF711

Blood: EDTA or ACD (Solution A or B):

• Adult: 5 mL
• Child: 5 mL
• Infant: 2-3 mL

Weekly

8 weeks

• Package and ship specimen to remain cold, but not frozen. 
• Ship via overnight express, using the FedEx priority overnight label provided. 
• Contact Client Services for shipping kits and instructions at (855) 535-1522.