Autoimmune hepatitis in genetic syndromes: A literature review

Table 1 Group-1: Disease gene is one of immunoregulatory genes

Genetic syndrome	Inheritance	Gene	Ref.	Number of AIH cases	Sex	Age at diagnosis	Nucleotide variant	Protein variant	Outcome
APECED/APS1	AD, AR	AIRE	Meloni et al[17], 2017	6	F; F; F; F; F; M	3 yr; 6 yr; 11 yr; 5 yr; 8 yr; 12 yr	c.[415C>T];[415C>T]	p.[(R139X)];[(R139X)]	Alive; Alive; Death; Death; Alive; Alive
			Huibregtse et al[7], 2014	1	F	10 yr	c.[20_115de196];[967_979del13]	p.[(?)];[(?)]	Alive
			Zaidi et al[18], 2017	2	M; M	3 yr; 5 yr	NR	NR	Alive; Death
IPEX	XLR	FOXP3	López et al[21], 2011	1	M	4 yr	c.[748-750delAAG];[0]	p.[(250Kdel)];[(0)]	Alive
			Baris et al[22], 2014	1	M	3 yr	c.[816+5G>A];[0]	p.[(?)];[(0)]	Death
			Magg et al[23], 2018	1	M	3 yr	c.[816+2T>A];[0]	p.[(?)];[(0)]	Death
			Duclaux-Loras et al[20], 2018	3	M; M; M	4 wk; 4 wk; 3 wk	c.[751_753delGAG]];[0]; c.[1157G>A];[0]; c.[227delT];[0]	p.[(E251del)];[(0)]; p.[(R386H)];[0]; p.[(L76Qfs*53)];[(0)]	Death; Death; Alive
ICF2	AR	ZBTB24	von Bernuth et al[25], 2014	1	F	3 yr	c.[1222T>G];[1222T>G]	p.[(C408G)];[(C408G)]	Alive (not responding to therapy)
ICF1	AR	DNMT3B	Sterlin et al[24], 2016	1	M	5 yr	c.[2324C>T];[2324C>T]	NR	Alive
SPENCDI	AR	APC5	Briggs et al[26], 2016	3	F; F; F	9 yr; 3 yr; 6 mo	c.[725A>G];[725A>G]; c.[389+1G>A];[389+1G>A]; c.[131C>T];[712T>C]	p.[(H242R)];[(H242R)]; p.[(?)];[(?)]; p.[(T44M)];[(C238R)]	Alive; Alive; Alive
SDS	AR	SBDS	Veropalumbo et al[28], 2015	2	NR; NR	9 mo; 12 mo	c.[258+2T];[183-1847A>CT]; c.[258+2T>C];[183-184TA>CT]	p.[(?)];[(?)]; p.[(?)];[(?)]	Alive; Alive
SCID	AR	CD3γ	Tokgoz et al[30], 2013	1	F	12 yr	c.[IVS2-1G>C];[IVS2-1G>C]	p.[(?)];[(?)]	Alive

AIH: Autoimmune hepatitis; AD: Autosomal dominant; AR: Autosomal recessive; XLR: X-linked recessive; F: Female; M: Male; NR: Not reported; SDS: Shwachman-Diamond syndrome; SCID: Severe combined immunodeficiency; SPENCDI: Spondilocondrodisplasia; ICF: Immunodeficiency, centromeric instability and facial dysmorphism; IPEX: Immunodysregulation, Polyendocrinopathy, Enteropathy, X-linked syndrome; APECED: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy; APS1: Autoimmune polyglandular syndrome type 1.

Table 2 Group-2: Polygenic involvement of immune-mediated risk (unbalanced genomic disease)

Genetic syndrome	Inheritance	Chromosomal region	Ref.	Number of AIH cases	Sex	Age at diagnosis	Deletion breakpoints [build GRCh37/hg19]	Outcome
Down syndrome	IC	-	Ravel et al[32], 2020	1	M	29 yr	-	Death
SMS	AD, IC	del17p11.2	Yang et al[36], 2014	1	F	24 yr	chr17: 16,660,721-20,417,975 dn	Alive
PHMDS	AD	del22q13.31-qter	Bartsch et al[37], 2010	1	F	3 yr	-	Alive
del2q	IC	del2q33.1-q34	Le Coz et al[6], 2018	1	F	12 yr	chr2:197,942,576–209,522,220 dn	Alive

AIH: Autoimmune hepatitis; IC: Isolated cases; AD: Autosomal dominant; F: Female; M: Male; SMS: Smith-Magenis syndrome.

Table 3 Group-3: Association not directly related to the disease causative mutation

Genetic syndrome	Inheritance	Gene	Ref.	Number of AIH cases	Sex	Age at diagnosis	Nucleotide variant	Protein variant	Outcome
NS	AD	PTPN11	Quaio et al[38], 2012	1	M	19 yr	c.[836A>G];[=]	p.[(Y279C)];[(=)]	Alive
			Loddo et al[5], 2015	1	F	6 yr	c.[923A>G];[=]	p.[(N308S)];[(=)]	Alive
WD	AR	ATP7B	Ganesh et al[40], 2017	1	M	6 yr	c.[2906G>A];[2906G>A]	p.[(R969Q)];[(R969Q)]	Alive
			Santos et al[41], 2019	1	F	25 yr	N.R.	N.R.	Alive
H syndrome	AR	SLC29A3	Bloom et al[42], 2017	1	M	17 mo	c.[1087C>T];[1087C>T]	p.[(R363W)];[(R363W)]	Alive
FHL5	AR	STXBP2	Esmaeilzadeh et al[43], 2015	1	M	7 yr	c.[1247-1G>C];[1247-1G>C]	p.[(?)];[(?)]	Death
TSC	AD	TSC1	Di Marco et al[44], 2017	1	F	47 yr	c.[682C>T];[=]	p.[(R228*)];[(=)]	Alive
SCD	AR	HBB	Jitraruch et al[45], 2017	7	F; M; M; F; F; F; F	5 yr; 16 yr; 13 yr; 13 yr; 8 yr; 8 yr; 3 yr	c.[20A>T];[20A>T]	p.[(E7V)];[(E7V)]	Alive; Alive; Death; Alive; Alive; Alive; Death
			Zellos et al[46], 2010	1	F	25 yr	c.[20A>T];[20A>T]	p.[(E7V)];[(E7V)]	Death
			Hurtova et al[47], 2011	1	F	54 yr	c.[20A>T];[20A>T]	p.[(E7V)];[(E7V)]	Death
GD	AR	GBA	Ayto et al[48], 2010	1	F	51 yr	c.[1226A>G];[115+1G>A]	p.[(N409S)];[(?)]	Death
PLCA	AD	-	González-Moreno et al[50], 2015	1	M	36 yr	NR	NR	Alive
			Yan and Jin[49]	1	F	50 yr	NR	N.R.	Alive
PFIC3	AR	ABCB4	Oliveira et al[51], 2017	1	M	22 yr	c.[874A>T];[3680T>C]	p.[(K292*)];[(I1227T)]	Alive

AIH: Autoimmune hepatitis; AD: Autosomal dominant; AR: Autosomal recessive; F: Female; M: Male; NR: Not reported; NS: Noonan syndrome; WD: Wilson disease; FHL: Familial hemophagocytic lymphohistiocytosis; TSC: Tuberous syndrome; SCD: Sickle cell disease; GD: Gaucher disease; PLCA: Primary cutaneous amyloidosis; PFIC3: Progressive familiar intrahepatic cholestasis type 3.