Table 1.

Molecular Genetic Testing Used in ALPS

Gene 1ALPS TypeProportion of ALPS Attributed to Pathogenic Variants in GeneProportion of Pathogenic Variants 2 Detectable by Method 3
Sequence analysis 4Gene-targeted  5
CASP10 ALPS-CASP103%-6% 6, 75/5Unknown 8
FAS ALPS-FAS65%-70% 9, 10>90%3%-4%
ALPS-sFAS~15%-20% 11, 12
FASLG ALPS-FASLG<1% 137/7Unknown 8
UnknownALPS-U~20% 14NA
1.
2.

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

3.

Pathogenic variants listed in Human Gene Mutation Database (HGMD) considered to assess the proportion of variants detectable by each methodology

4.

Sequence analysis detects variants that are benign, , of , , or pathogenic. Variants may include small intragenic deletions/insertions and , , and variants; typically, or whole- deletions/duplications are not detected. For issues to consider in interpretation of results, click here.

5.

Gene-targeted detects intragenic deletions or duplications. Methods used may include , long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a -targeted microarray designed to detect single- deletions or duplications.

6.

Note that of the two pathogenic variants in CASP10 originally reported [], p.Val410Ile was subsequently determined not to cause ALPS [].

7.

In two individuals, ALPS was presumed to result from coinherited pathogenic variants in FAS and CASP10 that were hypothesized to cooperate in causing ALPS [].

8.

No data on detection rate of -targeted are available.

9.

Generally pathogenic variants occur in FAS. Homozygous / FAS germline pathogenic variants are also observed and are typically associated with a severe [, , , , ].

10.

Individuals with an inherited in addition to a second acquired pathogenic variant [], as well as individuals exhibiting somatic [, ], have been also described.

11.

Somatic pathogenic variants are observed in selected cell populations, including α/β-DNT cells [, , ], but rarely in other lymphocyte subsets and not in non-lymphocytes.

12.

Detection of FAS somatic pathogenic variants requires specialized genetic testing of α/β-DNT cells sorted by either flow cytometric immunophenotyping or by magnetic bead immunophenotyping.

13.

Homozygous or pathogenic variants in FASLG have been reported: individuals with pathogenic variants have especially severe disease []. A review of reported cases identifies a total of eight cases (including 2 sibs). In five of seven probands, ALPS was associated with homozygous FASLG pathogenic variants and an inheritance pattern (see Molecular Pathogenesis).

14.

Approximately 20%-25% of individuals with ALPS lack a genetic diagnosis [].

From: Autoimmune Lymphoproliferative Syndrome

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