for all blood relatives of patients who undergo full single gene sequencing, multigene panel testing or exome sequencing at Ambry Genetics and are found to have a pathogenic or likely pathogenic variant. No-cost testing of blood relatives must be completed within 90 days of the original report date. Whenever possible, more closely related relatives should be tested before more distant relatives.
Order NowMajor and minor criteria (see detailed list below) have been established based on the features of PHTS and are used for testing and clinical diagnostic criteria.1
Individuals with one or more of the following may be appropriate candidates for PTEN genetic testing:
PTEN mutations can be found in ~85% of individuals with CS, 65% of individuals with BRRS, and 20% of individuals with PS. Furthermore, gross deletions have been found in 10% of individual with BRRS and/or CS-like syndrome (clinical sensitivity).3
In the setting of an autism spectrum disorder, PTEN mutations have been reported in~5% of patients who also have macrocephaly, and another 12% of patients diagnosed with developmental delay or intellectual disability (clinical sensitivity).2
Ambry's PTEN analysis can detect >99.9% of described mutations in the gene, when present (analytic sensitivity).
PTEN coding exons 1-9 and well into the 5’ and 3’ ends of all the introns and untranslated regions are analyzed by sequencing. Gross deletion/duplication analysis determines gene copy number for coding exons 1-9. Clinically significant intronic findings beyond 5 base pairs are always reported. Intronic variants of unknown or unlikely clinical significance are not reported beyond 5 base pairs from the splice junction. Genomic deoxyribonucleic acid (gDNA) is isolated from the patient’s specimen using standardized methodology and quantified. Sequence enrichment of the targeted coding exons and adjacent intronic nucleotides is carried out by a bait-capture methodology, using long biotinylated oligonucleotide probes followed by polymerase chain reaction (PCR) and next generation sequencing (NGS). Sanger sequencing is performed for any regions missing or with insufficient read depth coverage for reliable heterozygous variant detection. Potentially homozygous variants, variants in regions complicated by pseudogene interference, and variant calls not satisfying depth of coverage and variant allele frequency quality thresholds are verified by Sanger sequencing. Gross deletion/duplication analysis of PTEN using read-depth from NGS data is also performed. Any copy number changes detected by NGS are confirmed by targeted chromosomal microarray and/or multiplex ligation-dependent probe amplification (MLPA).
1. Pilarski R, Burt R, Kohlman W, Pho L, Shannon KM, Swisher E. Cowden syndrome and the PTENHamartoma Tumor Syndrome; systematic review and revised diagnsotic criteria. J Natl Cancer Inst.2013; 105:1607-1616.
2. Herman GE, Henninger N, Ratliff-Schaub K, Pastore M, Fitzgerald S, McBride KL. Genetic testing in autism: how much is enough? Genet Med. 2007;9(5):268-74.
3. McBride KL, Varga EA, Pastore MT, Prior TW, Manickam K, Atkin JF, et al. Confirmation study of PTEN mutations among individuals with autism or developmental delays/mental retardation and macrocephaly. Autism Research. 2010;3(3):137-41.