SNP Shot: Genomic Insights

Subcortical band heterotopia is a developmental condition where neurons fail to reach their designated locations in the fetal brain during its early formation. The term "heterotopia" signifies "out of place." Typically, the cerebral cortex, which forms the brain's outer layer, exhibits a structured, multi-layered arrangement of neurons. However, in individuals with subcortical band heterotopia, some neurons intended for the cerebral cortex do not complete their migration. These neurons halt their journey prematurely and form band-like clusters of tissue in unintended brain regions. Because these bands are situated beneath the cerebral cortex, they are termed "subcortical." In most instances, these bands are symmetrical, appearing in corresponding locations on both the left and right sides of the brain.

This abnormal brain development leads to neurological complications in those affected by subcortical band heterotopia. The symptoms and their severity are influenced by the size of the bands and the degree of impaired development of the cerebral cortex. The range of symptoms includes severe intellectual disability and early-onset, generalized seizures (affecting both brain hemispheres) to normal intellect with later-onset, focal seizures (affecting only one brain hemisphere). Some individuals also experience weak muscle tone (hypotonia), impaired fine motor skills (e.g., difficulty using utensils), or behavioral issues. Subcortical band heterotopia is often diagnosed following brain imaging performed after the appearance of seizures, typically during adolescence or early adulthood.

Inheritance:

The inheritance pattern of subcortical band heterotopia depends on the underlying genetic cause. When caused by mutations in the DCX gene, it follows an X-linked inheritance pattern. The DCX gene resides on the X chromosome, one of the sex chromosomes. Females, possessing two X chromosomes, can develop the condition with a single altered copy of the gene in each cell, sometimes exhibiting milder symptoms compared to affected males. Males, with only one X chromosome, typically experience a more severe form of the condition, known as isolated lissencephaly sequence (ILS), when a mutation is present in their sole copy of the DCX gene. Most males with subcortical band heterotopia have a DCX gene mutation that arose spontaneously (not inherited) and is present in only some of their cells, a phenomenon called mosaicism. A hallmark of X-linked inheritance is that fathers cannot transmit X-linked traits to their sons. Conversely, when subcortical band heterotopia is caused by a mutation in the PAFAH1B1 gene, it typically arises de novo (not inherited) due to a mutation occurring after conception, resulting in mosaicism. This type of alteration is termed a somatic mutation. PAFAH1B1 gene mutations present in all of the body's cells (germline mutations) usually lead to ILS.