Summary: Researchers have identified 26 new genes associated with intellectual disability.
Source: CAMH
A step closer to personalized medicine for intellectual disability
Researchers at the Centre for Addiction and Mental Health (CAMH) and Queen’s University have identified 26 previously unreported genes linked to intellectual disability. Most individuals affected by intellectual disability do not receive a molecular diagnosis today, a gap that can limit clinical care and is associated with worse health outcomes and reduced life expectancy. This study advances genetic understanding and diagnostic potential for affected families.
The findings, published in Molecular Psychiatry, have immediate implications for diagnosis and clinical care, and they expand current knowledge of brain development and function. Several of the genes discovered show overlap with genes implicated in autism spectrum disorders, highlighting shared biological pathways.
“This is the largest study of its kind on intellectual disability to come out of North America,” said Dr. John Vincent, Senior Scientist and leader of the MiND (Molecular Neuropsychiatry and Development) Laboratory in the Campbell Family Mental Health Research Institute at CAMH. The project was co-led with Professor Muhammad Ayub of Queen’s University.
Intellectual disability affects more than 1% of children worldwide and is defined by significant limitations in intellectual functioning and adaptive behavior that impact day-to-day life. Many individuals with intellectual disability also show symptoms that overlap with autism spectrum disorders, and growing evidence points to shared genetic contributors.
The study analyzed 192 families from Pakistan and Iran in which more than one family member is affected. Intellectual disability in these families is often caused by autosomal recessive mutations, where an affected individual inherits a defective copy of a gene from each parent. Many of the families reported marriages between relatives (consanguinity), a practice found in parts of South Asia, the Middle East, and Africa. Studying consanguineous families and multiple affected members increases the ability to identify recessive disease genes that are harder to find in outbred populations.
The research team identified definite or candidate mutations or copy number variants in 51% of families, affecting 72 different genes. Of these, 26 genes had not previously been implicated in autosomal recessive intellectual disability. Some of the newly implicated genes carry loss-of-function mutations, while others have missense variants; among the novel findings are the first reported missense variants in BDNF and TET1 associated with intellectual disability. Transcriptional analysis indicated strong prenatal brain expression for many of the genes, underlining their potential role during early neurodevelopment.
Beyond gene discovery, the study demonstrates a practical strategy that can accelerate diagnostic yield: combining microarray genotyping, homozygosity-by-descent mapping, copy number variation analysis, and whole exome sequencing in consanguineous families. This combined approach produced a high diagnostic rate and can inform clinical genetic testing strategies for populations where consanguinity is common. The approach is also relevant to outbred populations because the identified genes and pathways often overlap with de novo gene sets implicated in other neuropsychiatric disorders.
Implications for diagnosis and care
One immediate clinical application is risk reduction through family screening and genetic counselling. Relatives who are unaffected could be tested to determine carrier status for identified mutations. This information can guide reproductive decision-making and counselling about the genetic risks associated with within-family marriages. The longer-term goal is to integrate these gene discoveries into broader diagnostic screening tools that are applicable to global populations, including regions where consanguineous marriage is uncommon. Ultimately, precise genetic diagnosis can support tailored clinical care and lay the groundwork for research into targeted therapies.
“Knowing which genes are involved is a major step forward,” Dr. Vincent said. “The next stage is to understand how these genes function in the brain and in biological pathways before treatment strategies can be developed.”
Funding: This study was funded by the Canadian Institutes of Health Research.
Source: Sean O’Malley, CAMH
Image source: Image provided in the public domain.
Original research: The study is reported in Molecular Psychiatry under the title “Mapping autosomal recessive intellectual disability: combined microarray and exome sequencing identifies 26 novel candidate genes in 192 consanguineous families.” The research describes the discovery of 26 new candidate genes for autosomal recessive intellectual disability and summarizes the combined genetic methods and clinical implications.
Abstract
Approximately 1% of the global population is affected by intellectual disability (ID), and most individuals currently receive no molecular diagnosis. Prior estimates propose more than 2,500 autosomal ID genes, with many cases resulting from autosomal recessive variants. By combining microarray genotyping, homozygosity-by-descent mapping, copy number variation analysis, and whole exome sequencing in 192 multiplex consanguineous Pakistani and Iranian families with non-syndromic ID, researchers identified likely causative mutations or CNVs in 51% of families across 72 genes, including 26 novel candidate genes. Novel loss-of-function and missense variants were reported, with prominent prenatal brain expression for many genes. The high diagnostic yield supports the clinical potential of this approach for populations with common consanguinity and indicates relevance for broader diagnostic efforts in outbred populations.