Table 1.

Molecular Genetic Testing Used in Alagille Syndrome

Gene 1, 2Proportion of ALGS Attributed to Pathogenic Variants in GeneProportion of Probands with a Pathogenic Variant 3 Detectable by Method
Sequence analysis 4Gene-targeted deletion/duplication analysis 5
JAG1 94.3% 688% 612% 6
NOTCH2 2.5 6<100% 61 individual 7
Unknown 83.2% 6NA

ALGS = Alagille syndrome; NA = not applicable

1.

Genes are listed in alphabetic order.

2.

See Table A. Genes and Databases for chromosome locus and protein.

3.

See Molecular Genetics for information on variants detected in this gene.

4.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications.

6.
7.

One individual with a 5.9-kb deletion including exons 31 and 34 has been reported after genome sequencing [Rajagopalan et al 2021].

8.

Individuals with a clinical diagnosis of ALGS but without a detectable pathogenic variant in either JAG1 or NOTCH2 have been hypothesized to have a pathogenic variant in JAG1 or NOTCH2 that is not yet detectable with current molecular genetic testing [Authors, personal observation]. It is also possible that another gene related to the Notch signaling pathway, or a variant in an untranslated regulatory region, may be responsible, although this has not yet been reported.

From: Alagille Syndrome

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