Genetic testing is the method of choice for confirming the diagnosis of Alagille syndrome (ALGS), which is caused by genetic alterations in the Jagged 1 (JAG1) gene, Notch 2 (NOTCH2) gene, or 20p12 chromosomal deletion.1
Genetic testing is reliable and reveals an ALGS-related mutation in almost 95% of patients who show clinical signs and symptoms.2 This method, performed by a health professional in a laboratory setting, involves extracting the cellular DNA and analyzing it to detect genetic changes that may cause the disease. If genetic testing reveals an ALGS-related gene alteration, the doctor may recommend testing the patient’s parents, siblings, and other family members.
Read more about ALGS genetics.
Genetic counseling is recommended, both prior to and after genetic testing, in order to discuss the implications of test results on the lives of the affected individual as well as their relatives.3
ALGS Genetic Testing Benefits
Identification of ALGS-related gene mutation through genetic testing can help in predicting patient outcome, risk of recurrence, and medical management.
Genetic testing can also reveal the genetic status of individuals (ie, relatives of an affected individual) who are at risk of having ALGS but are asymptomatic. This may help in early diagnosis and timely initiation of treatment and preventive measures.
If 1 or both parents have ALGS, prenatal genetic testing (DNA samples obtained during pregnancy) or preimplantation genetic testing (DNA samples obtained from embryos formed through in vitro fertilization) can help in the early diagnosis of ALGS in the fetus.
Many symptoms of ALGS may also be due to other conditions. Thus, identification of ALGS-related genetic alterations through genetic testing can help differentiate if the symptoms are due to ALGS or other conditions.4
Genetic Testing for Establishing Diagnosis
Depending on the clinical signs and symptoms an individual presents, a combination of gene-targeted testing and comprehensive genomic testing is used.5 When an individual manifests signs or symptoms of ALGS, gene-targeted testing can be used to determine which genes are likely involved. Gene-targeted testing can include serial single-gene testing or a multigene panel.
Serial Single-Gene Testing
In this approach, sequence analysis of the causative genes — JAG1 and NOTCH2 — is performed in a serial manner (complete testing of 1 gene before proceeding to the next gene) that detects small alterations within the genes such as deletions, insertions, missense mutations, nonsense mutations, and splice variants.
First, sequence analysis of the JAG1 gene is performed. If no mutation is found, gene-targeted deletion/duplication analysis is performed using multiplex ligation-dependent probe amplification (MLPA),6 chromosomal microarray analysis (CMA),7 or fluorescence in situ hybridization (FISH)8, to detect intragenic deletions or duplications. A complete cytogenetic study9 may be performed if a deletion of the entire JAG1 gene is identified, to determine the presence of a chromosomal aberration such as translocation or inversion. An expert may recommend a chromosomal microarray analysis (CMA) if the affected individual presents developmental delay or hearing loss in addition to the common ALGS signs and symptoms, suggestive of a chromosome deletion.
If no JAG1 mutation is identified by sequence or deletion/duplication analysis but the clinical signs and symptoms strongly suggest ALGS, then sequence analysis of the NOTCH2 gene is considered. Since no large deletions of NOTCH2 have been reported, deletion/duplication analysis is not performed.
To make the method cost-effective while limiting identification of alterations unassociated with ALGS, genetic testing can be performed using a multigene panel that includes JAG1, NOTCH2, and other genes of interest (those that allow differential diagnosis of ALGS). A multigene panel that includes sequence analysis and deletion/duplication analysis is recommended.
In the case of individuals who present clinical signs and symptoms of ALGS but do not have any of the known gene mutations, comprehensive genomic testing can be used to identify novel genetic alterations without the need to determine which genes are involved. Genomic testing can be done by exome sequencing10 or genomic sequencing.11 If exome sequencing does not reveal any genetic alterations, an exome array12 may be considered to detect exon deletions or duplications.
1. Alagille syndrome. National Organization for Rare Disorders. Accessed May 19, 2021.
2. Ayoub MD, Kamath BM. Alagille syndrome: diagnostic challenges and advances in management. Diagnostics (Basel). 2020;10(11):907. doi:10.3390/diagnostics10110907
3. Diagnosis for Alagille syndrome. National Institute of Diabetes and Digestive and Kidney Diseases. Accessed May 19, 2021.
4. Invitae Alagille syndrome panel. Invitae. Accessed May 19, 2021.
5. Spinner NB, Gilbert MA, Loomes KM, Krantz ID. Alagille syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews®. University of Washington, Seattle; 1993-2021. Updated December 12, 2019. Accessed May 19, 2021.
6. Definition of multiplex ligation-dependent probe amplification. National Cancer Institute. Accessed May 19, 2021.
7. Wallace SE, Bean LJ. Educational materials — genetic testing: current approaches. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews®. University of Washington, Seattle; 1993-2021. Updated December 12, 2019. Accessed May 19, 2021.
8. Fluorescence in situ hybridization (FISH). National Human Genome Research Institute. Accessed May 19, 2021.
9. Cytogenetic. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews®. University of Washington, Seattle; 1993-2021. Accessed May 19, 2021.
10. Exome sequencing. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews®. University of Washington, Seattle; 1993-2021. Accessed May 19, 2021.
11. Genome sequencing. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews®. University of Washington, Seattle; 1993-2021. Accessed May 19, 2021.
12. Exome array. GeneReviews®. University of Washington, Seattle; 1993-2021. Accessed May 19, 2021.
Reviewed by Kyle Habet, MD, on 7/1/2021.