Overview

Fanconi anaemia (FA), also known as Fanconi pancytopenia, is a rare genetic condition and an inherited form of aplastic anaemia, caused by mutations in genes involved in the DNA repair pathway. The DNA holds all the instructions for the body to work. Every tissue, organ, and system of the human body goes through a balanced process of cell division and cell death. Naturally, errors occur during this process, but our body has “fail-proof systems” to correct the errors. In Fanconi anaemia, the genes encoding the “repair systems” suffer mutations and impact the balance between cell division and cell death. The consequences are congenital anomalies, bone marrow failure (BMF), and a high risk to develop cancer early in life.^1,2

Genetic counselling helps the patient understand relevant facts about the genes causing the condition, the inheritance patterns and associated risks. This offers an educated perspective, enabling the counselled person to make informed decisions regarding their own health, their reproductive options, and their offspring’s genetic inheritance.¹

The prenatal diagnosis of Fanconi anaemia is required in case the parents are carriers of the mutated genes, and specific genetic tests are performed on the foetal cells. The genetic counsel plays an important role at the time of prenatal testing for FA, helping the parents understand the genetic result of their foetus and the implications of this result on their family.¹

This article aims to unfold the genetic counselling process and the prenatal diagnosis of FA.

What is Fanconi Anaemia (FA)?

Fanconi anaemia is a rare genetic condition, affecting 1 in 160 000 people around the world. There are 23 known FA genes involved in the DNA repair pathway. A compromised DNA repair system creates DNA damage and genomic instability, leading to abnormal cell death (apoptosis), or abnormal cell growth, leading to BMF, aplastic anaemia, congenital abnormalities, and increased susceptibility to develop cancer at a young age.^2,3

Physical signs of FA can be present at birth, or become evident in childhood. About 60% of the patients have at least a symptom at birth, such as low birth weight, characteristic cranio-facial features, skeletal anomalies (especially thumb, arm, hip), short stature, light-brown skin lesions called “cafe-au-lait spots”, heart, kidney, gastrointestinal, endocrine, and genital problems.² 

About 50% of the FA patients are diagnosed before the age of 10. The BMF causes blood problems in children around the age of 7 years, even earlier, if the condition is very severe. The BMF symptoms are dizziness, fatigue, chest pain, shortness of breath, flu-like symptoms, nosebleeds, petechiae, and excessive bleeding when injured. FA patients who are diagnosed as adults, frequently present leukaemia or squamous cell carcinoma.^2,4   

Diagnosis

The FA diagnosis is a complex process involving a detailed patient history, family history, clinical examination, laboratory, genetic testing and further investigations. The diagnostic process of FA requires a haematologist, a clinical geneticist, or a genetic counsellor to identify the appropriate genetic testing option. The prognosis of a patient suffering from FA and lacking a diagnosis is very poor, resulting in death before the age of 10.²  

Chromosome breakage test (CBT) is the FA gold-standard test and confirms the FA diagnosis and the DNA instability by showing the chromosomal fragility (breaks and rearrangements) after exposing the cells to certain chemical substances.^1,2,5,6

If the result is negative, no further testing is necessary, unless the patient has symptoms highly associated with FA. The patient might have a mosaic form of FA, and have normal cells circulating in the bloodstream because a “corrective event” occurred in the blood-forming-bone marrow. Other cells would still have the FA faulty genes, and CBT can be performed on skin or hair cells, and if positive, confirms mosaic FA.⁵

If the CBT result is positive, a specific FA gene panel is performed. Targeted gene panels screen the DNA for well-known FA genes. It is a fast method to diagnose FA when there is a high clinical suspicion of FA. If the gene panel test is negative, or the symptoms are not characteristic, next generation sequencing (NGS) is performed, such as whole exome or whole genome sequencing. Some genetic errors, such as larger deletions or duplications, can be detected with microarray (aCGH), multiplex ligation-dependent probe amplification (MLPA), or NGS with copy-number variant (CNV) detection.^2,4,7   

In case the CBT is inconclusive, NGS can detect gene variants causing other disorders with chromosome instability. 

The genetic result is the key to an accurate diagnosis, and plays a critical role in the clinical management of a patient with FA symptoms or related cancer. It is also the foundation for the genetic counselling process. 

Genetic counselling for Fanconi Anaemia

The genetic counsel is a discussion about the most appropriate genetic tests, genes and their implications. The medical, familial, and pregnancy histories are all relevant to the process. Once the genetic test results are available, the focus is on the inheritance pattern of the mutation, the reproductive options and the patient’s and family’s risk of developing cancer. The genetic counsel also provides research opportunities and available support resources. Usually, the patient is a child with FA, and the genetic counsel helps the family understand the causative genes and their effects, and may suggest testing the parents and the siblings. CBT and HLA matching assessment can identify if the siblings can be donors for stem cell transplant. In other cases, a couple might be carriers of FA mutations, so they would seek genetic counselling for reproductive planning.^1,2,4,6,8  

Family history

The patients’ medical and family history is important, because the family can be “healthy carriers” of a faulty FA gene. They don’t have FA, but they could pass the mutated gene to their children.\ Some specific ethnic groups appear to have more frequent cases. The Ashkenazi Jews inherit FA as often as one in 100 people. People from Africa, and Romani people from Spain also present a higher FA incidence. Consanguinity between the parents increases the risk of having a child with FA.^2,4,9,10 

Inheritance patterns in FA

Autosomal recessive inheritance

Over 90% of FA patients present mutations in the genes FANCA, FANCC, FANCG, or FANCD2. These mutations are usually inherited in an autosomal recessive way. In this case, only a person having 2 copies of the FA gene would be affected. In a family with an affected child, each sibling would have 25% chances to inherit 2 copies of the FA gene (and have the disorder); 25% chances to have normal copies (and be unaffected); and 50% chances to inherit one copy of the FA gene and be a carrier.^1,4,6 

Autosomal dominant inheritance 

In under 1% of cases, FA is caused by mutation in the FANCR/RAD51 gene, and is transmitted in an autosomal dominant way. The presence of a single copy of the abnormal gene is sufficient for a person to be affected. The chances to inherit this variant is very low, and the mutation usually happens “de novo” (the affected person is the first case in the family).^1,6 

X-linked recessive inheritance

In about 1% or 2% of cases, FA is caused by mutations in the FANCB gene. The inheritance pattern is a X-linked recessive. If the mutation carrier is a person assigned female at birth (AFAB), there are 50% chances with each pregnancy to pass on the mutation. If the child is a person AFAB, they will be carriers of the mutation, and if the child is a person assigned male at birth (AMAB), they will have the disorder. If the carrier is a person AMAB, their children will not inherit the mutation. ^1,2,4,6  

Mutation carrier

The BRCA2/FANCD1 gene is also associated with FA, and patients having this variant have an increased risk of developing cancer as children. The genetic counsel is important to BRCA2 carriers, because they have an increased risk to pass the gene to their offspring, who can develop FA. The risk is higher for carriers with Ashkenazi Jewish ethnicity.^1,4,6,11  

Prenatal diagnosis of Fanconi Anaemia

Alpha-fetoprotein

Common prenatal screening tests, such as the detection of alpha-fetoprotein (AFP) in the mother’s blood, can raise the suspicion of FA, but it is not a specific test for FA, and CBT on amniotic cells is the elective test to identify FA in the foetus.^2,12 

Ultrasound examination

Another screening test that could detect FA is the prenatal ultrasound (US) examination. An increased nuchal translucency can be detected during a 10-14 week pregnancy ultrasound screening. This is a common sign of an increased risk for chromosomal abnormalities. It is not specific to FA, but it may indicate FA, when accompanied by specific anomalies detected in the second trimester USG  examination. This would require further prenatal invasive testing, involving amniocentesis followed by CBT.^1,10,13 

Amniocentesis and chorionic villus sampling

When a couple already has an affected child, the causing mutation is probably known. If they are expecting another baby, prenatal invasive tests, such as amniocentesis or chorionic villus sampling (CVS), would offer the possibility to test the cells of the foetus with a targeted gene test, but it would also offer an opportunity to test if the foetus is a HLA match to the affected sibling, in case a HSCT is needed. If the mutation is not already known, CBT can be performed on the amniotic cells. Prenatal testing can also include MLPA on the amniotic cells. The results can be compared to the parent’s results.^1,4,10,14,15 

Preimplantation genetic diagnosis (PGD)

If a couple already has a child with FA, and wishes to have another baby, may choose in vitro fertilisation (IVF). The preimplantation genetic testing (PGT) provides the genetic diagnosis of the IVF-obtained embryo, before transferring it into the mother’s uterus. The HLA status of the embryo can also be found through this process. The chances of a couple to have an unaffected baby, and also a possible donor for their affected child, are less than 20%, so they may need many rounds of IVF-PGD. Each IVF-PGD pregnancy requires prenatal testing to confirm the results of PGT.^1,4 

Summary

Fanconi anaemia is an inherited form of aplastic anaemia and is caused by mutation in the genes involved in the DNA repair pathway. The gene mutations are variable and the patients show congenital physical anomalies, BMF, and have a significantly increased risk to develop cancer. The genetic counsel is very important in FA, because it provides a personalised, educated perspective about the disease, enabling the patient and their family to make informed decisions about their own health, their reproductive options and their children’s health. The genetic counsel is also valuable for the prenatal diagnosis of FA. The laboratory work and the ultrasound examination raise the suspicion of FA, and the genetic analysis of the foetal cells collected through amniocentesis or CVS delivers the FA diagnosis. FA is a severe genetic condition, but an early diagnosis and genetic counsel can make a difference for the patient and their family.