Chromosomal Diagnostic Test Allows for Early Diagnosis, Better Treatment Planning in Angelman Patients

A molecular technique, known as chromosomal microarray analysis, enables early diagnosis of several genetic neurodevelopmental disorders — including Angelman syndrome — and improved treatment management, according to a Chinese study.

The study, “Clinical Application of Chromosome Microarray Analysis in Han Chinese Children with Neurodevelopmental Disorders,” was published in the journal Neuroscience Bulletin.

Neurodevelopmental disorders are a group of complex and diverse conditions that include intellectual disability, global developmental delay, and autism spectrum disorders (ASDs), and affect 15 percent of children worldwide.

Diagnosis of these disorders is based on genetic testing or behavioral symptoms. However, due to their varied nature and frequent coexistence with other conditions, diagnosing them can be challenging.

Angelman syndrome is a genetic neurological disorder caused by the absence or malfunction of the maternally inherited copy of the UBE3A gene. About half of all Angelman patients are initially misdiagnosed.

While 70 percent of Angelman cases are caused by a deletion of a specific region of the maternally inherited chromosome 15, where the UBE3A gene is located, rare cases are caused by the abnormal presence of two paternal copies of chromosome 15, and none from the mother — called paternal uniparental disomy.

The deletion of that same chromosomal region in the paternally inherited copy leads to a different neurodevelopmental disorder called Prader-Willi syndrome, due to the loss of other genes present in that same region. Prader-Willi can also be caused by uniparental disomy, but of two maternal copies of chromosome 15.

Chromosomal microarray (CMA) is a high-resolution and cost-effective method that looks for missing (deleted) or extra (duplicated) chromosomal segments, which characterize several neurodevelopmental disorders.

It is being increasingly used in the U.S. and Europe for genetic testing of individuals with unexplained developmental delays/intellectual disabilities, ASDs, or multiple birth defects. Its results have been shown to help doctors improve treatment planning and to better predict disease progression.

CMA usage in China started late, and its impact on clinical practice remains poorly understood.

In this study, Chinese researchers analyzed CMA results of 434 patients with developmental/behavioral problems and evaluated their impact on patients’ treatment management.

Patients, of whom 371 were male and 63 were female, with an average age of 5.63 years, were enrolled at two clinical centers in Shanghai, and showed different degrees of developmental delays, intellectual deficiency, and/or ASDs. Blood samples were collected and analyzed through CMA.

Disease-causing genetic alterations were present in 59 patients (13.6%), and most abnormalities (70%) were found in children under the age of 2. Researchers noted that younger children with unspecific symptoms of developmental problems could have more than one disorder, underlining the need for CMA to be performed in these situations to clarify diagnosis.

Thirty-three genetic alterations were detected in more than one patient, and some were associated with syndromes caused by chromosomal abnormalities, including Angelman, Prader-Willi, DiGeorge, and Williams-Beuren syndromes.

Three patients had lost the chromosomal region involved in Angelman and Prader-Willi syndromes, and one patient had uniparental disomy for chromosome 15. CMA enabled early diagnosis in three of these patients.

After confirmation of either Angelman or Prader-Willi through additional diagnostic tests, several medical decisions were made, such as referrals to neurologists, further testing, and changes in medication.

CMA testing provided immediate clinical benefits at several levels for these patients. Almost all patients with genetic abnormalities (94.9%) benefited from “changed or optimized clinical actions, such as referral to specialists, further diagnostic tests, medication changes, and genetic consulting,” based on CMA results, the researchers wrote.

The authors recommend the use of CMA testing in children with unexplained developmental abnormalities, and believe patients will benefit from subsequent personalized treatment.

Larger studies need to be performed to “determine recommendations or guidelines for proper medical management based on CMA results and follow up the health outcomes of affected patients,” they concluded.