Study shows how motor delays and hypotonia can help clinicians diagnose genetic disorders in children early, while addressing the barriers some face in accessing these life-changing tests.
Study: Clinical factors associated with genetic diagnosis in suspected neurogenetic disorders in a tertiary care clinic. Image Credit: Chinnapong / Shutterstock
A recent study in the journal Genetics in Medicine investigated phenotypic or clinical factors related to genetic diagnoses among individuals with neurodevelopmental diseases (NDDs).
Based on these factors, researchers generated a decision tree to aid clinicians in identifying individuals likely to test positive on genetic tests.
Background
NDDs, including autism spectrum disorders (ASD), intellectual disability, and global developmental delays, are highly inheritable and affect patients throughout their lives.
Recent advancements in genomic testing have allowed more individuals with neurodevelopmental diseases to receive genetic diagnoses.
Studies report several genetic variants in NDDs. These variants include chromosomal rearrangements, deletions, insertions, copy-number (CNV), and single nucleotide variants (SNV).
Previous studies found that NDD patients with genetic diagnoses are likelier to develop comorbidities like gastrointestinal motility impairments, epilepsy, heart disease, kidney disease, and urinary problems than those without genetic diagnoses.
Similarly, ASD patients with genetic diagnoses have an increased likelihood of having motor delays than those with ASD but without genetic diagnoses.
About the Study
In the present study, researchers in the United States investigated clinical factors related to genetic diagnoses among individuals with neurodevelopmental diseases.
The study sample comprised individuals presenting to the University of California, Los Angeles (UCLA) Care and Research in Neurogenetics (CARING) tertiary care clinic.
The researchers retrospectively reviewed the neurodevelopmental charts of 316 individuals attending the clinic between January 2014 and January 2019. They categorized individuals according to genetic test reports.
The researchers obtained participant data from electronic medical records. Genetic tests included fragile X syndrome testing, chromosomal microarrays (CMA), mitochondrial deoxyribonucleic acid (DNA) testing, exome sequencing (ES), and single-gene sequencing.
Participants had suspected or known neurogenetic disorders and completed one or more genetic tests. Researchers extracted genetic variants from clinical reports and classified them as likely benign, likely pathogenic (LP), pathogenic (P), or variant of uncertain significance (VUS).
Based on the variants, the researchers divided the participants into the likely pathogenic or pathogenic group, the negative study group, and the ES-negative group.
The LP/P group included individuals with genetic test reports showing LP/P variants or other definite molecular diagnoses. The negative study group included individuals whose genetic tests showed no LP/P variant but may exhibit benign genetic variants, VUS variants, or no variant. ES negative group individuals completed ES without LP, P, or VUS variants.
The researchers examined the age at which individuals first sat, walked, spoke a word, and uttered the first phrase. They also analyzed histories of motor delays, hypotonia, language delays, seizures, neurological diseases, congenital heart diseases, attention-deficit hyperactivity disorder (ADHD), microcephaly, macrocephaly, head circumference, and early interventions.
Logistic regressions determined odds ratios (OR), controlled for age, ethnicity, and other variables such as socioeconomic status, measured by the area deprivation index (ADI). The classification and regression tree analysis (CART) identified variables that discriminate between individuals with and without a genetic diagnosis.
The team determined motor delays following the World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC) Act Early guidelines.
Early interventions included those received for developmental disorders before three years of age. Macrocephaly denoted an individual’s occipitofrontal circumference exceeding the mean by two standard deviations. Individuals with microcephaly had occipitofrontal circumferences two standard deviations less than the mean.
Results
Among 316 participants, 246 completed genetic testing, of whom 152 (62%) had an LP/P variant. The other 94 individuals had none, benign or a VUS variant (i.e., the negative testing group).
In the LP/P group, 62 individuals received genetic diagnoses, including 12 shared and 50 unique variants. The mean age of presentation was nine years.
Individuals with positive genetic test reports tended to be female and have histories of hypotonia, motor delays, early intervention, and congenital heart illness.
The CART analysis showed that 75% of individuals with motor delays received a genetic diagnosis. Among individuals without hypotonia, motor delays, walking age, and age at initial assessment were crucial predictors of genetic diagnoses.
Individuals with motor delays were likelier to have an LP/P variant than those without such delays compared to the negative (OR, 4.3) and ES-negative cohorts (OR, 6.0).
A one-month delay in walking age increased the likelihood of carrying an LP/P variant by 5% to 11%, reflecting a strong association with developmental milestones. Compared to the ES-negative group, language delays were also significantly related to the presence of LP/P variants (OR, 3.2).
The study reveals that hypotonia and motor delays are associated with genetic diseases in children with neurodevelopmental disorders. It suggests clinicians should screen for motor impairment and consider genetic testing for patients with hypotonia.
Socioeconomic Disparities in Genetic Testing Access
The study also highlighted disparities in access to genetic testing, influenced by socioeconomic factors. Participants who did not complete exome sequencing (ES) tended to live in neighborhoods with higher deprivation, as measured by the Area Deprivation Index (ADI). These patients were also more likely to have uncertain insurance status, making accessing advanced genetic testing harder.
This underscores the need for equitable access to genetic diagnostic services to ensure that all patients, regardless of socioeconomic status, can benefit from these advancements.
Future large-scale studies could create clinically beneficial decision support tools to stratify patients with NDDs for genetic testing, enhancing diagnostic accuracy and accessibility, especially for underserved populations.