Small deletions of the Y chromosome are found in 5-13% of men who are otherwise healthy but have abnormal sperm shape or movement, a low sperm count, or no sperm.
Neoplasia Chromosomal Microarray Analysis
Neoplasia chromosomal microarray analysis (CMA), is increasingly relevant in establishing a diagnosis and prognosis for people with cancer (e.g. Gunnarsson, et al. 2008). With a single test, CMA detects chromosome deletions, chromosome duplications and amplifications, and copy neutral loss of heterozygosity (LOH) across the entire genome.
Chromosomal microarray analysis is not recommended as a test method for post therapy follow-up or for minimal residual disease detection.
Constitutional Chromosomal Microarray Analysis
Chromosomal microarray analysis (CMA) can be used to diagnose genetic syndromes caused by chromosome deletions, chromosome duplications, or uniparental disomy (UPD). Examples include Down syndrome, DiGeorge syndrome, velocardiofacial syndrome, Williams syndrome, Prader-Willi syndrome, and unbalanced translocations.
It is typically the best diagnostic genetic test to begin with when:
- Fetal abnormalities are seen by ultrasound (ACOG Committee Opinion 581)
- There is an intrauterine fetal demise or stillbirth (ACOG Committee Opinions 581)
- A person has more than one abnormality not fitting with a known syndrome
- A person has developmental delay or intellectual disability
- A person has an autism spectrum disorder (ACMG Practice Guideline, 2010)
Ordering providers can choose whether or not variants of uncertain clinical significance are reported. The latter may be most useful for prenatal testing when ultrasound has been normal and the chance of a genetic abnormality is low. Wapner, et al. 2012 found that CMA revealed more clinically relevant chromosome deletions and duplications than did standard karyotyping, even when the reason for pursuing testing was maternal age or abnormal serum screening results.
Sample Reports
Panel on Demand
For the patient with a rare phenotype, when the constellation of clinical findings is not recognized as part of a known syndrome, yet the clinician investigator would like to investigate a particular set of genes that are known to contribute to a particular phenotype, “panel on demand” sequencing is a cost-efficient and precise approach to diagnostic testing for rare inherited disease. Examples of panels might include a neurodevelopmental gene panel, hereditary cancer panel, cardiomyopathy gene panel or others. Study of the custom panel of genes from the DNA of a single individual is used to identify sequence variants with a very low population frequency, with nucleotide conservation across species and likely pathogenic consequence. Testing of a family trio facilitates filtering of sequence variants and reduces the number of potential candidates by looking for the same sequence alteration in an unaffected parent(s).
The NCGL offers several options for Panel on Demand based on the number of genes in the Panel:
- Hyper Panel on Demand (201-500 genes)
- Super Panel on Demand (101-200 genes)
- Mega Panel on Demand (11-100 genes)
- Micro Panel on Demand (2-10 genes)
- Single Gene Sequencing
Use the web tool at https://ncgl.uwcpdx.org/panel-on-demand/ to add genes to create a custom panel.
See CPT Codes and Cost below for information on pricing.
Reflex to Exome Sequencing: If a causative or potentially causative variant is not identified by this exome panel test it is possible to order a REFLEX clinical exome. The full exome sequence will be analyzed as is done for our Clinical Exome Sequencing test using the data obtained from the exome panel test. Submission of parental samples, and or other family members may be needed to assist in the interpretation of sequence variants. Order REFLEX to EXOME SEQUENCING.
Exome Sequencing Re-analysis
For the patient with a rare phenotype in whom exome sequencing did not identify a pathogenic variant in the past, re-evaluation of the original NCGL exome sequence data is offered when significant technological advances in sequencing technology and interpretation tools has occurred. The clinician is encouraged to contact the NCGL laboratory director to request comparison of the technology at the time of earlier testing relative to the present. Review of stored exome sequence files may be the most cost effective way of repeating examination of individual exomes. Study of the exome from the DNA of a single individual is used to identify sequence variants with a very low population frequency, with nucleotide conservation across species and likely pathogenic consequence. Testing of a family trio facilitates filtering of sequence variants and reduces the number of potential candidates by looking for the same sequence alteration in an unaffected parent(s).
Exome Sequencing
EXOME SEQUENCING of a single individual: For the PROBAND with a rare phenotype, when the constellation of clinical findings is not recognized as part of a known syndrome, exome sequencing is the most cost-efficient and precise approach to diagnostic testing for rare inherited disease. Study of the exome from the DNA of a single individual is used to identify sequence variants with a very low population frequency, with nucleotide conservation across species and likely pathogenic consequence.
EXOME SEQUENCING TRIO: TRIO Exome sequencing is sequencing the entire exome of a proband and his/her parents. (as exome comparators) TRIO testing allows filtering of rare sequence variants and reduces the number of potential candidates by looking for the same sequence alteration in unaffected parent(s). The proband and parents may request reporting of rare sequence variants of medically actionable genes.*
EXOME SEQUENCING COMPARATOR: Comparator exome sequence is an adjunct to exome sequencing of the proband; usually the parents are comparators. Although individual rare variants are not reported for the comparator exome, using it only for comparison with the proband, the parent may request reporting of rare variants of genes known to be associated with adult disease for which medical action could alter outcome.*
*The American College of Medical Genetics and Genomics (ACMG) recommends that clinical sequencing laboratories return secondary findings in 59 genes associated with medically actionable conditions. (Kalia, SS et al Genetics in Medicine Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics (17 Nov 2016)
ADAMTS2 gDNA Testing
Dominant mutations in the ADAMTS2 gene have been identified in individuals with the Dermatosparaxis type of Ehlers-Danlos Syndrome, or EDS type VIIC. This type of EDS is characterized by unique skin findings: soft and very thin skin, fragile skin, stretchy skin, as well as easy bruising and joint hypermobility.
Please consult our Ehlers-Danlos Syndrome Test Guide for more information about when to test for mutations in ADAMTS2.
Caffey Disease Testing
Infantile cortical hyperostosis or Caffey disease is a dominantly inherited bone phenotype that is often identified in infancy with irritability, fever, soft tissue swelling and decreased movement of the involved limb. Radiographs reveal subperiosteal new bone formation without fracture. The hyperostosis of long bones, ribs or the mandible often resolves within months and may recur in childhood. The clinical description in more recent reported families includes short stature, compression fractures, scoliosis and genu varus. The disorder is associated with a c.3040C>T, p.Arg836Cys sequence variant, in exon 41 of COL1A1 The sensitivity of directed DNA sequencing of this region of COL1A1 in infants with the Caffey phenotype is roughly 90%. The mechanism by which the variant contributes to the phenotype is presently unknown.
In infants (or pregnancies) with normal directed COL1A1 sequencing, a second recurrent Caffey phenotype has emerged. In this population, the hyperostosis is prenatal in onset with many detected at premature delivery with poor lung maturation and stillbirth. Recurrence in siblings born to unaffected parents is observed in this group. Search for a genetic cause of this variable Caffey phenotype is ongoing.
Deletion/Duplication Analysis
The CDL tests for gene panels and single genes now include both sequence analysis and deletion/duplication analysis by next-generation sequencing (NGS) technology. There will be no extra charge for del/dup analysis, and the prices currently shown for sequence analysis apply.
Osteopetrosis Panel
The CDL offers a 14 gene panel examining genes associated with autosomal dominant and recessive forms of osteopetrosis (AMER1, CA2, CLCN7, CTSK, FAM20C, FERMT3, LEMD3, LRP5, OSTM1, PLEKHM1, SNX10, TCIRG1, TNFRSF11A, and TNFSF11). Osteopetrosis is a bone disease that results in unusually dense bones that are prone to fracture. Autosomal dominant osteopetrosis is the most common form, affecting approximately 1 in 20,000 individuals, and is also the milder form. The major features in these individuals include multiple fractures, scoliosis, arthritis, and osteomyelitis and typically begin to manifest in late childhood or adolescence.
Autosomal recessive osteopetrosis is a more severe form of the disorder with a frequency of approximately 1 in 250,000 individuals. Affected individuals have a high risk of fracture, even from minor bumps and falls and may have short stature, dental abnormalities, and hepatosplenomegaly. The abnormally dense skull bones can pinch cranial nerves resulting in vision and hearing loss. These individuals may also experience problems with abnormal bleeding and recurrent infections due to impaired bone marrow function.
This panel is recommended for individuals with possible autosomal dominant or recessive osteopetrosis.
ALPL gDNA Testing
Hypophosphatasia is disorder characterized by defective bone mineralization in the presence of low serum and bone alkaline phosphatase. The range of clinical features is from severe undermineralization and bowing of bone in the fetus to the onset of fractures only in later adulthood. There are six recognized forms determined by age of onset, severity and mode of inheritance (both recessive and dominant). Each form results from the presence one or two mutations in ALPL, the gene that encodes alkaline phosphatase, tissue—nonspecific isozyme (TNSALP).
IFITM5 gDNA Testing
OI type V is an autosomal dominant condition caused by a single mutation in the gene IFITM5. To date, all affected individuals have the same mutation that creates a new translation initiation site and adds 5 amino acids to the amino terminal end of the chain. There is marked clinical heterogeneity. In addition to increased bone fragility and fractures, the phenotypic features that define the condition include:
- Hyperplastic callus formation following fractures or surgical intervention
- Calcification of the interosseous membrane of forearms
- Radial head dislocation
- Absence of blue sclerae and dentinogenesis imperfecta
While genomic sequencing of COL1A1 and COL1A2 is the recommended first step in the laboratory evaluation of OI, the presence of these characteristic features in an individual with an OI phenotype, especially in the context of a dominant family history, may warrant that the test for OI type V by IFITM5 genomic sequence analysis be moved to the first tier.
For guidelines on the correct test to order and for pertinent references, consult the Osteogenesis Imperfecta Test Guide.
EDS type VII Testing
EDS type VII, the Arthrochalasia type, is characterized by congenital hip dislocation, joint hypermobility, soft skin with normal scarring, easy bruising, blue sclerae, small jaw, and hypertrichosis. It is typically identified in infancy.
Testing for Known Mutation/Familial Variant
The Collagen Diagnostic Laboratory (CDL) offers targeted testing for previously identified sequence variants in a variety of genes.
“Known mutation/variant testing” should be selected on our test requisition form if a sequence variant was previously identified in the family by the CDL (we tested an affected relative of the patient) or by another laboratory. Known mutation/variant testing may also be ordered for individuals who wish to have clinical laboratory confirmation of variants identified through research laboratories.
Please contact our laboratory genetic counselor (Dru Leistritz, MS, CGC, phone: 206-543-5464, dru2@uw.edu) in advance before submitting a request to test for a variant in a gene not on the CDL test menu. For non-CDL genes, we ask for:
- A positive control (there will be no charge to test the positive control)
- A copy of the original mutation/variant report
- As much advance notice as possible
Turn-around time (TAT) is 7-10 business days for variants in genes on the CDL test menu, and 10-14 business days for variants in other genes.
Prenatal Testing
The CDL offers targeted mutation analysis for a known familial mutation on prenatal samples (all genes) and full sequencing of the Osteogenesis Imperfecta genes (Dominant and Recessive) in pregnancies.
We ask that you notify the genetic counselor in advance (Dru Leistritz, 206-543-5464) before sending a prenatal sample. The turnaround time for prenatal testing is 5-7 days for known mutations and approximately 2 weeks for full sequencing.