Early genetic testing may reshape care for inherited connective tissue disorders in children

Early genetic testing is increasingly recognized as a crucial tool for improving long-term outcomes in children at risk for inherited connective tissue disorders such as Marfan syndrome or Loeys-Dietz syndrome. For pediatricians, who are often the first to identify families with hereditary cardiovascular risk, a structured approach to cascade testing, genetic counseling, and early intervention can significantly reduce morbidity while minimizing patient and family stress. In this Q&A, Rajani Aatra, MS, MSc, LCGC, discusses the clinical rationale for early testing, the role of primary care clinicians in referral and counseling, common misconceptions that hinder timely evaluation, and how emerging technologies—including whole genome sequencing and future gene-targeted therapies—may change management for pediatric patients.

Contemporary Pediatrics: How can early genetic testing in children with suspected inherited connective tissue disorders, such as Marfan or Loeys-Dietz syndrome, improve long-term outcomes?

Rajani Aatra, MS, MSc, LCGC: Children in a family with a known genetic mutation have a 50% chance of inheriting that mutation. Testing would exclude 50% of those children from needing life-long screening and the resulting stress. The other 50% who are positive can be monitored more closely. There are some prophylactic medications (such as beta blockers) that may be prescribed to slow the progression of aortic/arterial enlargement and improve overall prognosis. Knowing a child carries a mutation can also guide the choice of sports early (such as avoiding contact sports or engaging in heavy weightlifting) rather than taking them away from a sport as teenagers, which can be very difficult and has a great social and emotional impact on children. Adjustment to a diagnosis is easier at a younger age. Genetic testing also identifies phenocopies (children who may show mild signs but don’t carry the genetic variant) and prevents misdiagnosis.

Contemporary Pediatrics: What role do pediatricians play in identifying families who may benefit from cascade genetic testing, and when should they refer patients for counseling?

Aatra: Pediatricians are the first providers to evaluate children from at-risk families. Obtaining a family history (either verbally or through a history form) at a visit should include questions on inherited diseases and any genetic testing that may have been performed in the family. If positive, those children/families should be referred to a genetic specialist for counseling and to discuss whether genetic testing is the right choice for them. Some families with inherited disease may not be aware if genetic testing was performed in the affected relative or what the results were. They should still be referred to a genetics provider to discuss options.

Contemporary Pediatrics: For parents who learn their child has a pathogenic variant, how can genetic counseling help them navigate next steps for both the child and other family members?

Aatra: Knowing your child carries a familial pathogenic variant is a difficult adjustment. There is fear of the long-term implications of the diagnosis and management. A genetic counselor can help coordinate referral to other specialists as needed. There can be worry about risk to other children in the family, and the genetic counselor can help arrange for testing them. Genetic diagnosis carries the burden of guilt – maybe the parent the variant was inherited from, maybe the sibling who tested negative (survivor's guilt). A genetic counselor is trained in short-term crisis counseling and can help the family navigate this and make referrals to mental health professionals as needed.

Contemporary Pediatrics: What are some common misconceptions or barriers you encounter when discussing genetic testing with families, and how can pediatricians help address these?

Aatra: There are a few common misconceptions that pediatricians can address and clarify that would help families get the genetic care they need:

• People who look the same do not necessarily have the same genes. While there is genetics at play in familial resemblance, looking different from an affected parent does not mean the child does not carry the pathogenic variant. The only way to know is to do the actual genetic testing
• Genes do not skip generations. While there may appear to be people in the family who do not show symptoms in different generations, it does not mean the gene has been skipped. The only way to know is to test. Similarly, a gene can only be passed from parent to child, and if you do not have it, you cannot pass it on
• The risk of inheriting a gene for an inherited connective tissue disorder is 50% for each child. These are independent events, implying it is 50% for each child. If the first child inherited the variant, the chance for the next child is still 50%.
• Aortic diseases are inherited equally among males and females. While symptoms may present differently, the inheritance is always 50-50

Contemporary Pediatrics: How might advances in genetic testing and clinical trial availability change the management of inherited cardiovascular conditions in pediatric patients?

Aatra: Genetic testing is advancing from panel testing (sequencing the coding regions of genes known to be associated with the particular disorder) to Whole Exome Sequencing (sequencing the coding region of all known genes, about 20,000 genes) to Whole Genome Sequencing (sequencing all of the genome, coding and non-coding). Current panels can only identify pathogenic variants in a small subset of our families with connective tissue disorders. WGS will allow identification of more variants in non-coding and regulatory elements. There are currently gene therapy trials being conducted in adults with inherited cardiovascular disease that may soon be available in the pediatric population. Gene replacement, gene editing, and RNA-based therapies are active areas of research to treat gene-positive children prior to the onset of symptoms. The availability of pre-implantation genetic testing provides the option of testing embryos conceived by IVF prior to implantation.