Comparing traits of affected patients with unaffected family members may be useful

Geisinger Health System researchers I propose that instead of studying patients with the same clinical neurodevelopmental diagnoses, investigators should compare quantitative measurements of neuropsychological and neurobehavioral traits in affected patients and their unaffected family members.

Developmental disorders such as autism and intellectual disability, and the psychiatric disorders schizophrenia and bipolar disorder, share many microdeletions, such as in 22q11.2, and single gene mutations, as with NRNX1, write researchers in Lancet Neurology [De Lucaetal., 2013].

An example of the type of studies researchers propose is a collaboration between two research groups who assessed 285 individuals with large 16p11.2 deletions and performed detailed cognitive, psychiatric, and behavioral evaluations in 71 patients and 68 non-carrier controls from the same families.

Less than one-third of individuals met the criteria for intellectual disability, which researchers define as an IQ of 70 or lower. But when compared with unaffected intra-familial controls, full-scale intelligence quotient was two standard deviations lower in deletion carriers, 84% of whom had a variety of neurodevelopmental diagnoses, including autism spectrum disorders, ADHD, anxiety disorders, mood disorders, gross motor delay, and epilepsy [Zufferey et al., 2012].

A Question of Measurement

The research model suggested by the Geisinger team presents some difficulties because of the nature of intellectual ability tests, says Gene S. Fisch, PhD, Senior Biostatistician and Research Professor in the Department of Epidemiology at the New York University Colleges of Medicine and Dentistry in New York.

While there are universally accepted definitions for lengths, volumes, and weights of body parts and products, measures of intellectual ability, behavior, and social responsiveness aren't so easily categorized. Dr. Fisch takes issue with two of the instruments used in the study about 16p11.2 deletions by Zufferey et al because they reduce “multi-dimensional aspects of behavior” to a“unidimensional, equal interval [arithmetic] scale with no defined unit,” he notes.

Likewise, Gerard Berry, MD believes that a patient's developmental or neuropsychiatric disorder—and its severity—results from a much more complex set of circumstances.

Although researchers say each particular cause of a neurodevelopmental disorder—genetic, metabolic, teratogenic, idiopathic, infectious, hypoxic-ischemic, or traumatic—can manifest as a spectrum of impairments of varying severity, many other factors may be involved, says Dr. Berry, Director of the Metabolism Program at Boston Children's Hospital in Massachusetts.

“Point mutations and deletion of genes, microRNA, and regulatory sequences that cause complete lack of proteins or defects in catalytic and transport activities, or interfere with protein subunit interactions, as well as environmental factors, imprinting lesions, and epigenetic perturbations—all of these probably play a role in phenotypic expression,” Dr. Berry explains. Other likely factors include the particular brain regions that are subject to genomic disturbances and the timing of the resulting molecular lesions, he adds.

Larger genetic deletions generally result in more serious phenotypes, but a small deletion might result in more serious symptoms if some of these other factors are present, he adds. “For example, a simple Mendelian model would not likely explain why one family member with an NRXN1 gene deletion presents with schizophrenia in late adolescence, and another with a similar mutation presents with autistic spectrum disorder and absent language development in late infancy,” says Dr. Berry. “Such an array of variables does not lend itself to simple mathematical formulations.”

The authors' model of “using continuous quantitative measures to identify how important specific genetic mutations are in individuals and families” has merit, he adds, “but is only a beginning as complex problems likely require a multifaceted approach.”

While there are universally accepted definitions for lengths, volumes, and weights of body parts and products, measures of intellectual ability, behavior, and social responsiveness aren't so easily categorized.

Figure 1.

Distribution of full scale intelligence quotient (FSIQ) of 16p11.2 BP4-BP5 deletion carriers (gray bars), intrafamilial non-carrier relatives (control, blue bars), and general population (blue bell curve) is shown.