Case Examples

Malcolm is a 4 year-old who presents with developmental delay. When you obtain the developmental history, you learn that he had difficulty feeding and failure to thrive in infancy. Their mother tearfully recalls this and attributes his difficulties to her struggle with parenting. The pregnancy, newborn and social histories are otherwise unremarkable. During your exam you note hypotonia, mild microcephaly, and distinctive facial features.

You reassure Malcolm’s mother and explain that you suspect an underlying genetic condition. You order chromosomal microarray testing, and are careful to include on the requisition the primary findings of hypotonia, microcephaly, and developmental delay. In addition, although you do not recognize a specific syndrome, you mention on the requisition that you noted dysmorphic facial features.

The results of the CMA testing indicate a small deletion in the VPS13B gene. Mutations in this gene have been associated with Cohen syndrome (patient information; provider information), a rare autosomal recessive condition. Malcolm’s specific deletion has not been previously associated with Cohen syndrome. In fact, the laboratory notes in the report that the deletion is smaller than their usual threshold for reporting, and that carrier status for recessive disease would not typically be reported. However, the clinical information you provided suggests that Malcolm may be more than just carriers of Cohen syndrome.

Follow-up family studies of the VPS13B gene reveal that Malcolm inherited the deletion on one chromosome, and a sequence variant on the other chromosome. Without the clinical information you provided on the requisition, this diagnosis would have been missed.

You are able to counsel the family that there is a 25% recurrence risk in future pregnancies. Although the diagnosis is difficult for the family, Malcolm’s mother is relieved to know she did not cause his delay, and feels empowered by the availability of prenatal testing. The diagnosis also alerts you to the risk for retinochoroidal dystrophy and intellectual impairment, common features of Cohen syndrome. You refer Malcolm to an ophthalmologist for screening and help the family enroll in educational services.

Resources

• GeneReviews: Cohen Syndrome - GeneReviews provides expert summaries of medical and genetic aspects of many genetic conditions
• Genetics Home Reference: Cohen Syndrome – GHR provides family-friendly information about genetics and genetic disease from the National Library of Medicine
• Cohen Syndrome: We A.R.E. Cohen Syndrome – a patient support and advocacy group for individuals and families with Cohen syndrome

Learn More

• Deciding to test – When and why do I use CMA?
• Ordering – Ordering Logistics
• Apply Results – What does a positive result mean?

Suzie is a 7 year old female, who is seeing you for assessment of her developmental delay. She also has a history of hypotonia. She is accompanied to clinic by her mother, Marie, and maternal grandmother. Your assessment finds that she is functioning at the age of a 5 year old.

Family history: Suzie’s mother Marie has mild learning delays but no other major medical problems on her side of the family. Marie is unsure of the identity of Suzie’s father; he is one of two individuals with no known medical problems. Marie is no longer in contact with these individuals and is unsure of their family medical history. Marie also never met her own father (Suzie’s maternal grandfather) and has limited information about her family medical history.

CMA result: normal dosage and long contiguous regions of homozygosity

Interpretation

These results suggest that Suzie’s parents are related by blood (consanguinity). Possible explanations include:

• Marie was aware that Suzie’s father was related to her but did not wish to share this information. This may or may not have been a consensual relationship.
• Marie unknowingly had sexual relations with a related family member, such as a half-brother she had not previously met

Note: Labs will typically report the amount of homozygosity, which loosely correlates to the degree or relationship (e.g., first-degree, second-degree). However, the degree of relationship cannot always be accurately estimated especially in families with multiple consanguineous relationships. If degree of relationship is important to the counseling and care of your patient and his/her family, discuss the findings directly with the laboratory.

Implications for Suzie

Suzie does not have a chromosome abnormality, and these results do not confirm that there is a genetic cause for her features. However, consanguinity increases the chance for rare autosomal recessive disorders, which could explain Suzie’s features. CMA cannot identify the recessive gene involved, but the genes included in the regions of homozygosity provide a place to start the search. Additional genetic evaluation may identify features consistent with a recessive syndrome linked to a gene in the homozygous regions.

If Marie were still in a relationship with Suzie’s father, the couple should be counseled that additional offspring have up to 25% chance of having features similar to Suzie. Because chromosomes randomly distribute and recombine with each conception, risk for additional recessive conditions cannot be ruled out.

Resources

• Rehder CW, David KL, et al. American College of Medical Genetics and Genomics: standards and guidelines for documenting suspected consanguinity as an incidental finding of genomic testing. Genet Med. 2013 Feb;15(2):150-2.
• Bennett, R.L., Motulsky, A.G., Bittles, A., Hudgins, L., Uhrich, S., Doyle, D.L., et al. Genetic Counseling and Screening of Consanguineous Couples and their Offspring: Recommendations of the National Society of Genetic Counselors. J Genet Couns, 11(2): 97-119 (2002). - Reaffirmed September 2009

Program Links

• Pre-test counseling – What do families need to know?
• Applying results – Other results

Adult-onset condition

CMA was ordered to try to identify an underlying cause for 5 year-old Emily’s autism and mild developmental delay. Results indicate a deletion on chromosome 17 that includes the BRCA1 gene. Loss of function of BRCA1 is associated with significantly increased lifetime risk for breast and ovarian cancer. The lab’s interpretation of the microdeletion indicates that it has been associated with developmental delay.

Emily’s parents are unlikely to have this deletion because they do not exhibit autism or cognitive disability. However, parental testing is indicated because the deletion in Emily may have resulted from a balanced chromosome rearrangement in a parent. A balanced rearrangement means that the normal amount of genetic information is present, but in a different location than usual. A carrier parent would not demonstrate Emily’s features, but the rearrangement could interrupt the BRCA1 gene, increasing cancer risks for the parent as well. If inherited, other family members are also at increased risk. The family’s increased risk for cancer may not have come to light without this testing, and the information enables you to refer them for genetic counseling, cancer screening and preventive management.

You present the results to Emily’s parents who are quite confused and upset.

“I thought we were doing this test to figure out why Emily has her current problems. Now we also have to worry about her developing cancer, and we can’t do anything about it. If we had known that this kind of result could come back, we might not have had testing.”

Occasionally, even if you were careful to counsel a family prior to testing about the risk for incidental findings, these unexpected results come as a shock. The family may not remember all of the information you discussed prior to testing, or may have been so hopeful for a diagnosis they diminish the risks of testing. Providing printed information for the family to take home from their first visit can reinforce pre-test counseling. When disclosing results, patience and empathy can diffuse initial reactions. It is important to clarify misconceptions, such as the availability of preventive interventions for cancer. Reframing the result as an opportunity and outlining a specific management plan can help families regain a sense of control.

You remind the family that CMA detects genetic changes that involve more than one gene, and therefore may affect more than one part of the body. You acknowledge that this surprising information is hard to hear, and reinforce that it can empower the family to manage both Emily’s autism and her risk for breast cancer. You assure them that there are steps that can be taken to reduce cancer risks and that screening is available for early detection. You also stress that these concerns are many years down the road for Emily, since BRCA1 related cancers do not typically affect children. You recommend parental testing for chromosome rearrangements, and refer the family for genetic counseling.

Resources

• GeneReviews: BRCA1 and BRCA2 - provides expert summaries of medical and genetic aspects of many genetic conditions
• Reiff M, Bernhardt BA, Mulchandani S, Soucier D, Cornell D, Pyeritz RE, Spinner NB. "What does it mean?": uncertainties in understanding results of chromosomal microarray testing. Genet Med. 2012 Feb;14(2):250-8.

Learn More

• Pre-test counseling
• Post-test counseling
• Applying Results – What does a positive result mean?

Joey, 6 years old, presents with mild intellectual disability and behavioral issues, including increasing issues with attention and anxiety. Although he has an IEP in place, Joey is having increasing trouble in the classroom, socially and academically. He has had limited testing to determine the cause of these challenges. You order CMA, which identifies a microdeletion on chromosome 7 consistent with a diagnosis of Williams syndrome.

Based on the results, Joey’s educational interventions can be better targeted to match the cognitive profile associated with individuals with Williams syndrome. For example, individuals with Williams syndrome may experience challenges with distractibility, visual memory, abstract reasoning, and sensory input.

Additionally, the diagnosis of Williams syndrome helps direct appropriate medical management. Affected individuals are at increased risk for complications in multiple body systems, including cardiac, gastrointestinal, urinary tract, musculoskeletal problems, and endocrine problems. Having this information allows for appropriate referrals for evaluation and management.

While Joey’s parents are relieved to have a diagnosis, they read up on Williams syndrome and are concerned about the future. They express to you the tension between wanting an answer and not wanting the answer they get. Individuals with Williams syndrome do not get better. They continue to have significant social and medical issues throughout life. Initially, they express a desire to go back to when everyone thought Joey was just a little slow.

As with many diagnostic tests, families may have emotional responses to CMA results. The communication skills you use for other patient interactions, including empathy and realistic reassurance, will apply to counseling about CMA testing. Reinforcing how test results can be used to guide management is often empowering for families.

After validating their feelings, you reinforce that Joey’s parents have the skills to care for him. You reassure them that together you will develop a plan to manage the developmental and medical issues Joey will face. You explain that the diagnosis allows you to tap into a wealth of information about this well-described syndrome. After hearing about the specialists and interventions that are available, Joey’s parents can appreciate how the diagnosis will enable access to more help. You also suggest that they connect with other families of children with Williams syndrome, and you direct them to the Williams Syndrome Association website. You encourage them to have hope that they can create a “new normal” after this diagnosis.

At follow-up one year later, Joey’s family reports that they have seen dramatic improvement in school after a more focused IEP was implemented. They have become active in the Williams Syndrome Association, and are grateful to have the support of other families whose children are so similar to Joey. They have diligently followed-through on all the referrals you recommended, and thus far Joey has not had any major complications.

Resources

• Perspectives on Williams syndrome from affected individual, parent, and scientist (NPR, 2005)
• Overview of Williams syndrome (NPR, 2010)
• Family perspective on Williams syndrome (NPR; 2010)
• Science behind the personality of Williams syndrome (NPR, 2010)
• Genetic education materials for schools success - provides information about medical/dietary needs, education supports, behavior & sensory support, physical activity & trips & events, school absences & fatigue, emergency planning, and resources for a select number of genetic conditions
• GeneReviews: Williams Syndrome – provides expert summaries of medical and genetic aspects of many genetic conditions

Program Links

• Deciding to test – What does CMA detect?
• Apply Results – What does a positive result mean?
• Post-test counseling

Justin, 6 months old, comes to clinic for a developmental evaluation. His parents have no concerns about his progress, but are very concerned about the results of a CMA that was ordered shortly after birth because of a cleft palate and VSD. The CMA results show a small deletion that includes a gene involved in brain development, which is weakly linked with autism. The lab interprets this as a variant of unknown significance, stating that there is not currently enough information to determine whether it is benign or pathogenic.

Justin’s parents have a lot of questions about what to do with this unexpected information.  They’ve been asking their pediatrician whether and when they should start autism services and interventions.  They are very confused and have gotten a lot of conflicting information on-line about how to approach this situation. 

Justin’s mom expresses her frustration with the situation, “It made sense to have the test [CMA] at the time.  We were worried about the cleft palate and hole in the heart.  We wanted to make sure there was nothing else wrong with him.  No one told us that the test might tell us about other things that were unrelated, like autism.  I watch him all the time now – is he interacting with his environment like other kids his age or is autism starting? It’s so hard.” Justin’s parents want to have more children, and they ask whether they should have prenatal testing for this variant in a future pregnancy.

Pre- and post-test counseling  helps families prepare for and adjust to uncertainty. Some families may have difficulty accepting that a result is not a necessarily a cause of a child’s features. Teaching about the commonality of genetic variation in the general population can help families put uncertain results in perspective. Other families express relief and erroneously believe that a genetic condition has been ruled out. For these families, it is important to communicate that ongoing research could identify a variant as pathogenic, or that other tests could identify a cause.

While rare, uncertain results can be frustrating for providers and families alike. Many families find hope in the fact that the classification of a variant may change over time as other individuals with the variant are identified. Reframing a VUS result as an opportunity to be more vigilant can give them increased sense of control.

You perform parental studies, and Justin’s father is found to be a carrier of the same variant. A screen for features of autism spectrum in Justin’s father is negative. There is no other family history of autism spectrum disorders or birth defects. This evaluation makes it less likely that the variant is pathogenic. However, you explain that some uncertainty remains because genes contributing to autism may be expressed differently in different individuals. Other unknown genetic and environmental factors are likely to contribute to autism as well. Since the variant could be benign, you do not recommend prenatal testing in a future pregnancy, which could be expensive or risky without providing clear prognosis for the baby.

Although the family is reassured by the parental evaluations, you discuss a plan to monitor Justin’s development closely so that any necessary interventions can be implemented early. The family leaves feeling grateful that the CMA result will mean their child will not fall through the cracks if signs of autism emerge.

Resources

Reiff M, Bernhardt BA, Mulchandani S, Soucier D, Cornell D, Pyeritz RE, Spinner NB. "What does it mean?": uncertainties in understanding results of chromosomal microarray testing. Genet Med. 2012 Feb;14(2):250-8.

Learn More

• Applying results – Other results
• Post test counseling – What do families need to know? How do I support families?

Watch the video of Megan's story about her daughter with Phelan-McDermid syndrome.

Megan O’Boyle discusses her family’s journey to finding a diagnosis for her daughter and its impact. CMA can detect changes that are not identifiable by standard karyotypes and can also help better define deletions and duplications that are initially identified on a karyotype.

“When people ask why would I want this additional diagnosis, it really isn’t an additional diagnosis, my answer is that we have a fantastic support group and when you know you are missing a specific piece of your chromosome-22q13, you can get a lot of specific information that doesn’t apply to the gigantic umbrella that we know as autism.”

Mrs. O’Boyle’s story demonstrates the importance getting a specific diagnosis can have for relieving guilt and finding a community.

 “…if there is a genetic abnormality, it frees the family from a tremendous guilt that many families with an autism diagnosis are given…One of the greatest things that a geneticist said to me…[was] that there was nothing that I could have done to cause this.”

Resources

• Phelan-McDermid Foundation
• GeneReviews: Phelan-McDermid Syndrome

Program Links

• Deciding to test – When and why do I use CMA?
• Apply Results – What does a positive result mean?
• Post test counseling – How do I support families?