SNP Shot: Genomic Insights

Opitz G/BBB syndrome is a genetic disorder affecting the body's midline development. The name "G/BBB" is derived from the initials of the surnames of the families in which the syndrome was first identified, while "Opitz" refers to the physician who initially described its characteristics. There are two main types: X-linked Opitz G/BBB syndrome and autosomal dominant Opitz G/BBB syndrome. These types are distinguished by their different genetic causes and inheritance patterns, although their signs and symptoms are generally similar.

A hallmark of Opitz G/BBB syndrome is widely spaced eyes (ocular hypertelorism). Individuals with this condition often experience abnormalities in the larynx, trachea, or esophagus, leading to difficulties in swallowing or breathing. These throat issues can result in recurring pneumonia or even life-threatening respiratory problems. Laryngeal cleft, a gap between the trachea and esophagus allowing food or fluids into the airway, is a common defect. The size of the cleft can vary, and infants may have trouble breathing during feeding. Most males with Opitz G/BBB syndrome exhibit genital abnormalities such as hypospadias (urethra opening on the underside of the penis), cryptorchidism (undescended testes), an underdeveloped scrotum, or a bifid scrotum (scrotum divided into two lobes). These genital differences can cause urinary tract problems.

Approximately half of individuals with Opitz G/BBB syndrome experience mild intellectual disability and developmental delays. This can manifest as delayed motor skills (e.g., walking), speech delay, and learning difficulties. Some individuals may also exhibit characteristics of autism spectrum disorders, impacting communication and socialization. Around 50% of affected individuals have a cleft lip, sometimes accompanied by a cleft palate (opening in the roof of the mouth). Others may have only a cleft palate. Less frequent features, affecting fewer than half of those with the condition, include minor heart defects, imperforate anus (blocked anal opening), and brain abnormalities like a small or missing corpus callosum (the connection between the brain's hemispheres). Recognizable facial features can include a prominent forehead, widow's peak, flat nasal bridge, thin upper lip, and low-set ears. The presentation of these features can vary significantly, even among family members.

Inheritance:

When caused by mutations in the MID1 gene, Opitz G/BBB syndrome follows an X-linked inheritance pattern. This is because the MID1 gene is located on the X chromosome, one of the sex chromosomes. Males, with only one X chromosome, will develop the condition if that single copy of the MID1 gene is mutated. Females, with two X chromosomes, may experience milder symptoms or no symptoms at all if only one copy of the gene is affected. Because it is rare for females to have two mutated copies of MID1, they often only display hypertelorism. In X-linked inheritance, fathers cannot transmit X-linked traits to their sons.

In rare instances, Opitz G/BBB syndrome is inherited in an autosomal dominant pattern, meaning only one copy of the mutated gene is needed to cause the disorder. These cases are linked to mutations in the SPECC1L gene or deletions of genetic material on chromosome 22. Males and females with autosomal dominant Opitz G/BBB syndrome typically exhibit similar symptom severity.

In both X-linked and autosomal dominant forms, some individuals inherit the genetic change from an affected parent. Other cases arise from new, spontaneous mutations, occurring in individuals with no family history of the disorder.