Course:MEDG550/Student Activities/DiGeorge Syndrome

DiGeorge Syndrome (OMIM#188400) is the name of a recognizable clinical syndrome that is characterized by heart abnormalities, deficiencies in the immune system, distinct facial features, cleft lip and/or cleft palate, thyroid problems, and an increased risk of learning disabilities and psychiatric illnesses.

The majority of patients with DiGeorge Syndrome have a genetic change called a microdeletion on chromosome 22. A microdeletion is when a small portion of the chromosome is deleted. On chromosome 22, the portion that is deleted contains genes that are important for development. The position of the microdeletion is 22q11.2, which means it is on the long arm of chromosome 22 at position 11.2. Rarely, DiGeorge Syndrome can also be caused by microdeletions on chromosome 10, specifically at 10p14-13.

Before the genetic cause was discovered, this disorder was known by several different names such as velocardiofacial syndrome (VCFS) (OMIM#192430), Shprintzen syndrome, CATCH 22, and conotruncal anomaly face syndrome. All of these conditions are due to a microdeletion on the same area of chromosome 22 and are now collectively referred to as "22q11.2 microdeletion syndrome" (OMIM#611867). This article will focus on the features and genetics of 22q11.2 microdeletion syndrome, not the rarer causes of DiGeorge Syndrome such as deletions on chromosome 10, and refer to this specific type of DiGeorge Syndrome as "22qDGS."

Clinical Features

The deleted portion of chromosome 22 contains many different genes that are important for growth and development of the embryo . The 22q11.2 microdeletion is known as a contiguous gene syndrome, where 2 or more genes in a row are deleted, meaning that different parts of the body can be affected depending on what genes are missing. 22qDGS can be extremely variable in terms of what each individual's clinical features are, and can range from mild to severe.

Human chromosome 22 with the DiGeorge Syndrome region indicated.

Common Signs and Symptoms

• Cleft palate
• Distinct facial features
• Heart abnormalities
• Immune system deficiencies and autoimmune disorders
• Feeding problems
• Breathing problems
• Kidney abnormalities
• Low calcium in the blood
• Seizures
• Hearing loss
• Problems with speech and language
• Increased risk of mental illnesses and learning disabilities

Intelligence and Learning

Intelligence of individuals with 22qDGS is variable, and 30-40% of individuals have mild intellectual disability. Developmental delay is common, especially when speech and language are developing in young children. There are often issues with non-verbal communication and these may present as problems with memory, attention, visual-spatial skills and math. Concerns with intelligence and learning may have an impact on individuals' communication, social, and living skills. Individuals with 22qDGS tend to have strengths in rote verbal learning and memory, reading decoding, and spelling.

Mental Health

Psychiatric diseases are a common feature of 22qDGS that occur later in life, and are often of greatest concern to parents and families because of their serious and challenging nature, as well as the social stigma associated with them. Approximately 20-25% of individuals with 22qDGS will be diagnosed with schizophrenia, which usually develops in late adolescence to early adulthood. Anxiety, bipolar disorder, and attention deficit disorder are also common and autism spectrum disorders are found in 20% of individuals with 22qDGS.

Genetics and Prevalence

22qDGS syndrome is an autosomal dominant condition, meaning that it affects males and females equally and that only one 22q deletion is needed to show signs of the disorder. 85% of individuals are missing a region on chromosome 22 of approximately 3 million bases of DNA or 40 genes, and the remaining 15% of individuals have a smaller area deleted, but still are regarded to have 22q11.2 microdeletion syndrome.

In 85-93% of cases, this is a de novo mutation in the individual, meaning that it is a new microdeletion and not present in the parents. De novo mutations are due to chance, they are caused by random changes in the egg or sperm, or in early development of the embryo and are not caused by anything that the parents did. Parents who have a child with a de novo chromosome 22 deletion have a less than 1% chance of having another baby with 22qDGS.

The other 7-15% of people with 22qDGS inherited the deletion on chromosome 22 from one of their parents. If a parent has a 22q11.2 deletion, they have a 50% chance of passing the chromosome with the deletion to each child. If a child inherits the deletion, they will develop 22qDGS, and as mentioned before, this condition is extremely variable. It is known that all people who inherit a 22q11.2 deletion will show signs of the condition, but it is not possible to predict how severe the disorder will be in a given person.

At the population level, 22qDGS occurs in 1/4000 to 1/6000 births worldwide..

Diagnosis

FISH Analysis of 22q11.2 microdeletion syndrome

If an individual shows symptoms of 22qDGS, a genetic diagnosis can be made by using specific technology to determine if there is a deletion on chromosome 22. Chromosomes can be thought of as books. The human genome is made up of 46 books, 23 are inherited from each parent. Inside these books are instructions for growth and development. When an individual is suspected to have 22qDGS, the most common technology used to search for a deletion in chromosome 22 is chromosomal microarray (CMA). CMA is a technology that is capable of detecting any extra or missing DNA on chromosomes. In other words, CMA is scanning all 46 books and is looking for any extra or missing pages inside. In those with 22qDGS, the number of pages missing from chromosome 22, or book 22, varies from person to person. Regardless, CMA can detect 85-90% of these deletions. If there is a known deletion in a family, or the exact number of pages missing has been confirmed, more targeted testing methods can be employed to test for this same deletion in other family members. Fluorescence in situ hybridization (FISH) is one of these more targeted tests. This technique is equivalent to using the “control F” or “find” function on a computer. It searches for specific DNA sequences in the genome, or pages in a specific book, to determine whether they are present are absent.

Treatments and Management

Since so many parts of the body are affected by 22qDGS, a wide range of health care specialists can be needed for ongoing issues in patients. Cardiologists, endocrinologists, immunologists, occupational therapists, audiologists, opthamologists, speech pathologists and psychiatrists are among the many professionals that may be needed to care for and monitor patients with 22qDGS. Early diagnosis in children may lead to early interventions which have better prognosis for speech and language development.

Genetic Counselling

If there is a family history of 22qDGS, a couple can meet with a genetic counsellor to determine their risk for having a child with the condition. Ultrasound indicators, such as the presence of a congenital heart defect or cleft palate , may also warrant a meeting with a genetic counsellor. The genetic counsellor can discuss the options of genetic testing on an ongoing pregnancy to determine if the fetus is at risk of developing the condition.

Non-Invasive Prenatal Testing

Non-Invasive Prenatal Testing (NIPT) can be used to detect chromosomal abnormalities in pregnancies, including the 22q11.2 microdeletion. NIPT is non-invasive to the pregnancy, requiring a blood draw from the mother. The test looks at placental DNA in the maternal circulation and the absence or presence of the 22qDGS. NIPT is a screening test, and a confirmation of 22qDGS in a pregnancy would require a diagnostic procedure such as chorionic villus sampling or amniocentesis.

CVS and Amniocentesis

For a diagnostic result in a pregnancy, a sample of the placenta or amniotic fluid must be taken through a chorionic villus sampling (CVS) or amniocentesis. A CVS procedure can occur between 11-13 weeks of gestation, and is sampling the early placenta. Amniocentesis can occur after 15 weeks gestation, and is sampling the amniotic fluid that contains fetal cells such as skin or lung cells. Both procedures are considered invasive, and come with a risk of miscarriage so it is important to consult a health care professional to discuss the risks and benefits of this procedure. A couple may choose to have genetic testing on the pregnancy to make decisions about whether to stop or continue the pregnancy, change the management and delivery of a pregnancy with 22qDGS, or prepare to care for a child with 22qDGS.

Preimplantation Genetic Diagnosis

In a family where there is a known diagnosis of 22qDGS, such as one parent with 22qDGS, couples wanting to have a child can have pre-implantation genetic diagnosis. This is form of in vitro fertilization, a procedure where ooctyes are retrieved from the female and fertilized by the male's sperm to create an embryo. After approximately 5 days of growth, one cell is removed from the growing embryo and genetically tested to determine if it has the same chromosome 22 deletion running in the family. The couple can then chose to implant embryos that do not the 22q11.2 microdeletion.

In vitro fertilization can be an expensive and emotional decision for families, and consultation with health care professionals such as genetic counsellors can help determine if the use of preimplantation genetic diagnosis is warranted depending on the specific family history of 22qDGS.

Support groups and specialty clinics

• Google map of global 22q deletion support groups
• The International 22q11.2 Foundation Inc. (based in USA)
• Chromosome 22 Central (Central-Eastern US and Canada)

Clinics in Canada:

• Canadian Adult Congenital Heart Network (Canada-wide)
• Dalglish Family Hearts and Minds Clinic For 22q11.2 Deletion Syndrome (Toronto General Hospital)
• 22q Deletion Syndrome Clinic (Hospital for Sick Children, Toronto)

Clinics in the USA:

• 22q and You Center (Children's Hospital of Philadelphia)