HJAR Mar/Apr 2025

AUTISM CARE 22 MAR / APR 2025 I  HEALTHCARE JOURNAL OF ARKANSAS known to be implicated in autism is rising exponentially, with over 800 susceptibility genes having been recognized. It is likely that, in many cases, multiple genes, each with a small effect size, contribute to the etiology of autism. Understanding the con- tribution of these genes is challenging, and at this time, predictive risk scores for autism are not precise enough to be used in clinical practice. Since 2013, the American College of Medical Genetics and Genomics (ACMG) practice guidelines for an evaluation of autism recommends a tiered approach to evaluation, with first tier testing to include fragile X testing and chromosomal micro- array in the absence of a suspected specific syndrome. 14 Second tier testing includes MECP2 and PTEN testing and a brain MRI when indicated. This tiered approach is esti- mated to identify an etiology in 30-40% of individuals. 14 More recently, theACMG rec- ommends whole exome/genome sequenc- ing as a first or second tier testing for individuals with congenital anomalies, intel- lectual disabilities, or developmental delay, which could include autistic individuals. 15 Genetic testing for autism has many advantages, such as informing medical management and treatment, early recogni- tion of medical conditions associated with genetic syndromes, and providing accurate recurrence risk estimates to parents. Despite these benefits, a minority of autistic individ- uals are offered and receive genetic testing. Anumber of factors likely contribute to this, including limited awareness by healthcare providers about the benefits of and recom- mendations for genetic testing for autism, lack of genetic providers, and lack of insur- ance coverage. Continued education and increased access to genetic testing is there- fore imperative. n PTEN mutation can be detected in about 10-20% of people who have both autism and macrocephaly. 7 Neurofibromatosis type 1, caused by mutations in the NF1 gene, is characterized by skin pigment change and neurofibromas. Twenty-five percent of children with neurofibromatosis type 1 are autistic. 8 Syndromes that cause autism can also be due to chromosomal aberrations. Williams syndrome (7q11.23 deletion) causes devel- opmental delay, hypotonia, intellectual dis- ability, cardiovascular disease, and unique personality characteristics. Ten to 20% of people withWilliam syndrome are autistic. 9 Smith-Magenis syndrome (17p11.2 deletion) causes developmental delay, sleep distur- bances, intellectual disability, and a behav- ior phenotype that includes self-injurious behaviors. Autism is also present in 50-75% of people with Smith-Magenis syndrome. 10 Deletions of 22q11.2 cause a wide range of symptoms that vary in severity, even within the same family. Autism is present in 20%, and other common features include con- genital heart disease, palate abnormalities, immune deficiencies, and learning diffi- culties. 11 Deletions of 16p11.2 cause devel- opmental delay, psychiatric conditions, motor speech and language disorder, obe- sity, motor coordination difficulties, and autism/autistic features in 20-25%. 12 Both deletions and duplications of 1q21.1 cause developmental delay, intellectual disability, and autism, however, deletions are often associated with craniofacial dysmorphisms and congenital anomalies, while duplica- tions are typically associated with macro- cephaly. 13 Many other chromosomal aber- rations are known to cause autism. Overall, a genetic cause of autism can be determined in about 25% of people, leav- ing a large portion of individuals without an identifiable cause. 3 The number of genes estimates range from 70-80%, making autism one of the most genetically deter- mined neurodevelopmental disorders. 2 Some individuals with an autism diag- nosis also have additional medical, devel- opmental, or behavioral features due to a genetic disorder, often described as “syn- dromic autism.” While autism may be a common feature in people with certain genetic disorders, syndromes overall only account for approximately 5% of people with autism. 3 Many of these syndromes are monogenic, and genetic testing is relatively straightforward. Examples include fragile X syndrome, tuberous sclerosis, Rett syn- drome, Cowden syndrome, and neurofibro- matosis type 1. Fragile X syndrome is due to a trinucleotide repeat expansion in the FMR1 gene. Individuals with fragile X syn- drome are generally male and often have developmental delay, intellectual disability, and behavior issues and may have cranio- facial features that become more obvious with age. Approximately 50-70% of people with fragile X syndrome are autistic. 4 Tuber- ous sclerosis, caused by mutations in the genes TSC1 or TSC2, causes benign tumor growth in various areas of the body, most commonly the skin, brain, kidneys, heart, and lungs. Autism occurs in 16-61% of peo- ple with tuberous sclerosis. 5 MECP2 gene mutations cause a spectrum of pheno- types, one of which is Rett syndrome. Rett syndrome typically occurs in females and is characterized by regression in motor skills and language, which starts between 6 and 18 months of age. Sixty-one percent of females with Rett syndrome are autistic. 6 Cowden syndrome is one of several syndromes caused by PTEN mutations. Individuals with Cowden syndrome have an increased risk for benign and malignant tumors of the breast, thyroid, kidney, and endometrium. Macrocephaly is usually present, and a