Abstract
Purpose: This study aimed to identify phenotypic factors associated with genetic diagnoses in patients with neurodevelopmental disorders and generate a decision tree to assist clinicians in identifying patients most likely to receive a positive result on genetic testing.
Methods: We retrospectively reviewed the charts of 316 patients evaluated in a neurodevelopmental clinic between 2014 and 2019. Patients were categorized based on genetic test results. Analyses were performed to identify variables that discriminate between patients with and without a genetic diagnosis.
Results: Patients with a genetic diagnosis were more likely to be female and have a history of motor delay, hypotonia, congenital heart disease, and early intervention. Classification and regression tree analysis revealed that 75% of patients with motor delay had a genetic diagnosis. In patients without motor delay, hypotonia, age of walking, and age at initial evaluation were important indicators of a genetic diagnosis.
Conclusion: Our findings suggest that motor delay and hypotonia are associated with genetic diagnoses in children with neurodevelopmental disorders. The decision tree highlights patient subsets at greater risk and suggests possible phenotypic screens. Future studies could develop validated decision trees based on phenotypic data to assist clinicians in stratifying patients for genetic testing.
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Article In Brief
A chart review of 316 children and adolescents revealed that mild to severe motor delays and being female strongly predicted that testing would show the existence of a genetic mutation. And while genetic testing is now more common, disparities in access to those tests remain.
Children with neurodevelopmental delays who tested positive for a genetic mutation were more likely to be female and have a history of motor delays, low muscle tone, congenital heart disease, and a history of early interventions, according to an Oct.10 study in Genetics in Medicine.
Neurodevelopmental specialists at the Care and Research in Neurogenetics (CARING) Clinic at the University of California, Los Angeles, who carried out the chart review of 316 children and adolescents, said that genetic testing of children with these phenotypic factors is important in understanding the cause of their delays. These children also could be referred to clinical studies of these rare genetic variations that could ultimately lead to targeted treatments.
“One of the goals in neurodevelopmental medicine is to move into a more personal approach for each of our patients,” said Aaron D. Besterman, MD, health sciences associate clinical professor in the department of psychiatry at the University of California in San Diego. He was previously a neurodevelopmental genetics fellow at UCLA, where the work was carried out. A child and adolescent psychiatrist, Dr. Besterman is now a clinical investigator at the Rady Children's Institute for Genomic Medicine.
“Genetic testing allows us to identify a specific genetic cause,” he said, adding it is now standard of practice to order genetic testing and family counseling for children with developmental disorders. But insurance companies still have a say in what genetic tests they will pay for, and there remains a lot of variability in genetic testing, he noted.
The children and young adults ultimately seen at the CARING clinic are sicker and have complex histories, said Dr. Besterman. The families are desperate and welcome a detailed genetic screen to figure out the cause of their child's disabilities.
“Initially, the question we asked ourselves was whether we were recruiting patients into the CARING clinic because we thought they had a genetic disorder or whether there were clinical characteristics in children with an identified genetic disorder,” he said.
They were able to identify unique factors in those who tested positive on a genetic screen, which he said “should help clinicians decide who should be prioritized for genetic testing.”
It is now suspected that at least 30 percent of children with a neurodevelopmental disorder, including autism, intellectual disability, and global developmental delay, would have a positive genetic test. Hundreds of rare genetic variants are tied to these disorders. Genetic testing is now more common, but disparities in access to testing remain.
Chromosomal microarray (CMA) can identify copy-number variants, which seem responsible for 10 to 20 percent of children with neurodevelopmental problems. Exome sequencing (ES) also identifies single-nucleotide variants and can bring a diagnostic yield of more than 40 percent if both tests are ordered. Patients with a genetic disorder often have other medical problems, including gastrointestinal mobility, epilepsy, heart disease, and kidney/urinary problems, that factor into the level of care they require. This is the first study looking at risk factors for a genetic diagnosis conducted in tertiary care centers, said Dr. Besterman.
“There have been other studies that tested a broader population of children with neurodevelopmental disabilities, and our small study replicated the findings from these larger studies. Motor delays, mild to severe, and being female strongly predicted a positive genetic finding,” the child psychiatrist said.
Study Design, Findings
The UCLA team conducted a chart review on 316 patients seen at the CARING clinic from 2014 to 2019, separating children and young adults based on the results—positive or negative—of their genetic tests. Then, the scientists used a computer model to identify phenotypic variables in those with and without a genetic diagnosis. (There was incomplete genetic testing in 70 patients, and they were not part of the analysis.) Their charts included information on when the children sat up, crawled, and walked. They looked for language delays, including when the children said their first word (after a year) and phrase (after two years); whether the electronic medical record included a history of motor delay, hypotonia, seizures, congenital heart, any neurological diagnosis, ADHD, macrocephaly, microcephaly, or abnormal head circumference; and whether they were referred for early intervention and if they were younger than 3 years old at the time.
Of the 246 patients with completed genetic testing, 152 patients (61.8 percent) were found to have a genetic variant. There were 62 genetic diagnoses based on the testing. Only a dozen genetic conditions were shared by two or more patients.
The most robust differences between those who tested positive and those who didn't were being female and having a history of motor delays. In this population, 75 percent of patients with motor delays had a genetic diagnosis. Even without having a formal motor delay, those with hypotonia, the age at which they started walking, and an earlier age of intervention were also important indicators of a positive genetic test. (The scientists created three cohorts: those who tested positive, those who tested negative, and others who tested negative if they had CMA and ES genetic tests.) The genetic tests varied in the cohort, including CMA, FMR1 CGG repeat analysis, metabolic testing, PTEN testing, mitochondrial DNA testing, and MECP2 testing. Thirty-three of the negative cohort group also had ES testing. Interestingly, for every month's delay in walking (recalled by the caregiver), the child's chance of having a positive genetic test increased by 5 to 11 percent. A history of hypotonia, congenital heart disease, and early intervention also independently increased the odds of having a positive genetic test. Language delays were also associated with a higher risk for a genetic mutation.
The scientists did not observe differences between the two negative cohorts. When they looked at the genetic tests, they found that people living in lower socioeconomic neighborhoods were less likely to have had an ES test. This test is more expensive, insurance companies might deny coverage, and the families might not have the means to pay for genetic testing.
The CARING clinic was launched by Julian Antonio Martinez, MD, PhD, associate professor in the department of human genetics and the department of pediatrics at UCLA, and Shafali Spurling Jeste, MD, chief of the division of neurology and co-director of the Neurological Institute at Children's Hospital Los Angeles, to offer more help to children with neurodevelopmental problems. Dr. Jeste also is a professor of neurology and pediatrics at the Keck School of Medicine of the University of Southern California.
The clinician-scientists said a more extensive prospective study is necessary to replicate the findings. If genetic testing resources are limited, then knowing who is at higher risk—in this case, girls with motor deficits—will help decide who would benefit most from genetic testing. Now, whole genome sequencing is available, and older tests might not be necessary.
Neurodevelopmental specialists believe that knowing that there is a genetic explanation for their child's symptoms is important for families. “Clinicians can explain to families that there is a genetic reason why their child has the symptoms they do. While insurance companies by law can't discriminate against a genetic illness, life insurance companies can,” Dr. Besterman said. He recommends that families who want life insurance make arrangements before genetic testing.
https://journals.lww.com/neurotodayonline/fulltext/2024/12050/clinical_factors_that_preclude_genetic_testing_in.3.aspx/?cid=eTOC+Issues.2024-neurotodayonline
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