Highly Unusual Form of Inheritance Seen in Immune Disorder
Researchers at Fox Chase identify a child who received both copies of a disordered gene from his mother, with no contribution from the father
PHILADELPHIA, PA (June 11, 2012)—The biological rule that people receive half of their genetic material from their fathers and half from their mothers does not always apply, it seems.
In the first such case on record, researchers at Fox Chase Cancer Center in Philadelphia have identified a child with a severe form of immune deficiency due to having received two copies of a disordered gene from his mother. Indeed, the child inherited two entire copies of the same chromosome, made up of thousands of genes, from his mother alone, with no contribution from his father.
The problem for this child, explains David L Wiest, PhD, a professor at Fox Chase and senior author on the study, is that the chromosomes he inherited from his mother contain certain gene mutations, as is true for most people; however, in this case those mutations are not counterbalanced by normal copies of those genes inherited from the father, since both copies came from the mother.
"This type of inheritance is not something many scientists and clinicians think about," says Wiest, whose results will be published online June 11, 2012 in the Proceedings of the National Academy of Sciences. "But it's something experts should consider in any inherited disorder where only one parent appears to carry a mutation, because it can lead to additional health problems in the future."
In this instance, the child developed Severe Combined Immunodeficiency (SCID), a life-threatening disease in which the body cannot produce the blood cells needed to fight off infections. This disease typically occurs when a mother and father each pass along one copy of a mutated gene, or in “X-linked inheritance” when the mother passes a mutated gene on the X chromosome to her male offspring. An X-linked form of inheritance would cause SCID in boys, who have only one X chromosome; in girls, a normal copy of the same gene on their other X chromosome would prevent the disease from manifesting.
But it's often difficult to determine how children inherited SCID. "In many cases where the causative mutation is unknown, it is difficult to know what the inheritance mechanism is," says Wiest. In one case he and his colleagues examined closely, a five-year-old boy was found to have two copies of a mutated gene that caused SCID in the patient, but the researchers could not find the mutation in his father. "That was surprising," recalls Wiest. "I thought, 'How could this be?' It baffled me."
Looking more closely, they saw that something highly unusual had occurred: The child had inherited two copies of the entire chromosome 1 – the largest chromosome in the body – from his mother alone. People have 23 pairs of chromosomes in every cell, with each parent contributing one of the chromosomes in each pairing. In this case, however, the son had two duplicate copies of his mother's chromosome 1, with nothing from his father.
Unfortunately, this meant all of the mutations and other genetic anomalies typically found in chromosomes could not be counteracted by normal copies from the other parent. Here, the boy developed SCID, which was successfully treated by a bone marrow transplant. But his chromosome 1 carried 16 other genes where both copies inherited from the mother were predicted to either not be expressed or had mutations that destroyed their function. Because these disabled genes are found in all of the child’s tissues, it is possible that he may develop additional disorders in the future, Wiest explains.
This is the first time this mode of inheritance has been identified in someone with SCID, but scientists have documented it in other genetic disorders such as Prader-Willi syndrome.
"We thought it was important to publicize this case, so people who care for SCID patients can be aware of this mode of inheritance," says Wiest. "Even if such a patient’s SCID is under control, he or she will require greater surveillance, as future complications may arise as due to alterations in other genes."
Wiest’s coauthors from Duke University include Drs. Joseph L. Roberts, Rebecca H. Buckley, Jinwook Shin, and Xiao-Ping Zhong. His coauthors from Fox Chase are Drs. Jianming Pei and Joseph R. Testa (Cancer Biology), Qiong Wei and Roland Dunbrack (Developmental Therapeutics), and Biao Luo, Alla Lapidus, and Suraj Peri from the Cancer Genome Institute at Fox Chase Cancer Center.
The work was supported by the Institute for Personalized Medicine at Fox Chase Cancer Center, the National Institutes of Health, the National Cancer Institute, and funding from Pennsylvania’s Commonwealth Universal Research Enhancement (CURE) program.
Fox Chase Cancer Center, part of Temple University Health System, is one of the leading cancer research and treatment centers in the United States. Founded in 1904 in Philadelphia as one of the nation’s first cancer hospitals, Fox Chase also was among the first institutions to receive the National Cancer Institute’s prestigious comprehensive cancer center designation in 1974. Fox Chase researchers have won the highest awards in their fields, including two Nobel Prizes. Fox Chase physicians are routinely recognized in national rankings, and the Center’s nursing program has achieved Magnet status for excellence three consecutive times. Fox Chase conducts a broad array of nationally competitive basic, translational, and clinical research and oversees programs in cancer prevention, detection, survivorship, and community outreach. For more information, call 1-888-FOX-CHASE (1-888-369-2427).