Genotype–Phenotype correlations of SCARB2 associated clinical presentation: a case report and in-depth literature review

Atasu, Burcu; Acarlı, Ayse Nur Ozdag; Bilgic, Basar; Baykan, Betül; Demir, Erol; Ozluk, Yasemin; Turkmen, Aydin; Hauser, Ann-Kathrin; Guven, Gamze; Hanagasi, Hasmet; Gurvit, Hakan; Emre, Murat; Gasser, Thomas; Lohmann, Ebba

doi:10.1186/s12883-022-02628-y

Table 2 Clinical and Genetic Characteristics of the Reported AMRF-Associated Families

From: Genotype–Phenotype correlations of SCARB2 associated clinical presentation: a case report and in-depth literature review

Genetic findings				Clinical characteristics
Type of the variant	Pathogenic Variant	Zygosity	Localization on the protein	Age at onset^a	Age at death^b	Myoclonus^a	Tremor^a	Ataxia^a	Dysarthria^a	Seizure	Renal involvement/ FSGS^a	PNP	Additional clinical manifastations	Reported families/ affected individuals	Etnicity	Ref
Nonsense	c.533G > A; p.W178X	HM	GC binding domain	16 ± 1.4 (15, 17)	25.5 ± 2.1 (23, 26)	16 ± 1.4 (15, 17)	NR	17.5 ± 0.7 (15, 18)	+	NR	19.5 ± 2.1 (18, 21)/-	-	Slowed horizontal saccadic eye movements	1/2	Portuguese	[7]
Splicing	c.1239 + 1G > T	HM	Lumenal domain	22	NR	32	25	32	32	NR	28/ +	-	NR	1/1	Turkish-Cypriot	[5]
Frameshift	c.435_436insAG; p.W146SfsX16^c	HM	Lumenal domain	9	32	29	21	+	+	+	9/ +	NR	NR	1/1	Scottish	[5]
Frameshift/ Splicing	c.296 delA; p.N99IfsX34 /c.704 + 5G > A	CH	Lumenal domain/ Lumenal domain	19	NR	24	19	26	26	+	20/NR	NR	NR	1/1	British	[5]
Nonsense	c.862C > T; p.Q288X^c	HM	GC binding domain	20 ± 4.4 (17, 18, 25)	29.7 ± 5 (29, 25, 35)	23 ± 2 (21, 23, 25)	20 ± 4.4 (17, 18, 25)	+	+	+	22.5 ± 0.7/NR (17, 18, 30)	NR	NR	1/3	French Canadian	[5]
Missense	c.1087C > A; p.H363N	H^f	Lumenal domain	26	NR	26	NR	27	NR	+	-	-	NR	1/1	NR	[11]
Splicing	c.1116‑2A > C	HM	Lumenal domain	14	29	14	NR	17	NR	+	15/NR	NR	NR	1/1	Italian	[12]
Splicing	c.704 + 1G > C	HM	Lumenal domain	15	27	15	NR	16	NR	+	12/NR	NR	NR	1/1	Italian	[12]
Frameshift	c.1258delG; p.E420RfsX5	HM	Lumenal domain	23	33	23	NR	24	NR	+	10/NR	NR	NR	1/1	Italian	[12]
Frameshift	c.666delCCTTA; p.Y222X	HM	GC binding domain	25	40	25	NR	31	NR	+	15/NR	NR	NR	1/1	Italian	[12]
Splicing/ Missense	c.424‑2A > C/ c.1087C > A; p.H363N	CH	Lumenal domain/ Lumenal domain	5.5	NR	26	26	26	NR	+	5.5/NR	NR	NR	1/1	Italian	[12]
Nonsense/ Frameshift	c.862C > T; p.Q288X^c/ c.1187 + 3insT	CH	GC binding domain/ Lumenal domain	16	NR	16	NR	NR	+	+	-	+	NR	1/1	French Canadian	[13]
Frameshift	c.111delC; p.I37MfsX7	HM	Lumenal domain	18 ± 3.6 (14, 20, 20)	34.3 ± 3.5 (31, 34, 38)	20 ± 6 (14, 20, 26)	NR	18 ± 3.6 (14, 20, 20)	NR	+	+ /NR	+	Hearing impairment, dilated cardiomyopathy	1/3	German	[14]
Splicing	c.704 + 1G > A	HM	Lumenal domain	21	NR	23	23	21	25	+	25/NR	NR	Hearing loss	1/1	Australian	[15]
Frameshift	c.1015insT; F339FfsX9	HM	Lumenal domain	22	NR	22	22	30	30	NR	-	NR	Slowed saccades, myoclonic status	1/1	NR	[16]
Frameshift	c.1385_1390delinsATGCATGCACC; p.G462DfsX34	HM	TM domain	46.6 ± 4 .7 (43, 52, 45)	+ (NR, NR, 59)	52 ± 13.8 (43, 68, 45)	+ (NR, 57, 48)^e	48.3 ± 4 (44, 52, 49)	50.6 ± 6.5 (44, 57, 51)	+ (58, 63, NR)^e	-/NR	NR	Dementia [17]	2/3	Japanese	[17, 18]
Nonsense	c.361C > T; p.R121X	HM	Lumenal domain	20	28	20	+	+	+	+	-	-	Cognitive impairment	1/1	Japanese	[18]
Nonsense	c.1270C > T; p.R424X	HM	Lumenal domain	20.5 ± 4.7 (17, 17, 21, 27)	+ (17, 17, NR, 27–34)	+	+	+	+	+	-/NR	NR	Mild generalized skeletal muscle atrophy (34)	2/4	Arab [19], NR [20]	[19, 20]
Splicing	c.995‑1G > A	HM	Lumenal domain	20.5 ± 0.7 (21, 20)	NR	20.5 ± 0.7 (21, 20)	NR	20.5 ± 0.7 (21, 20)	+	+	-	NR	Pes cavus, Mild generalized skeletal muscle atrophy	1/2	Chinese	[21]
Splicing	c.1187 + 5G > T	HM	Lumenal domain	19	NR	19	19	19	+	+	-	+	NR	1/1	Chinese	[22]
Frameshift	p.L14PfsX35	HM	TM domain	19	NR	19	+	27	27	+	+ /NR	NR	NR	1/1	Arab	[23]
Frameshift	c.134delA; p.N45MfsX88	HM	Lumenal domain	20 ± 4.2 (17, 23)	NR	21.5 ± 3.5 (19, 24)	20 ± 4.2 (17, 23)	+	NR	+	+ /NR	+	NR	1/2	Turkish	[9]
Frameshift/ Splicing	c.434_435dup?/ c.704 + 5G > A	CH	Lumenal domain/ Lumenal domain	19	NR	19	19	+	NR	-	+ /NR	NR	NR	1/1	British or Irish	[24]
Frameshift	p.L31RfsX6	HM	Lumenal domain	27	NR	27	+	30	30	-	-	NR	NR	1/1	Gambian	[25]
Splicing	c.423 + 1G > A	HM	Lumenal domain	20.5 ± 2.1^d (22, 19)	NR	32 ± 2.8 ^d (34, 30)	20.5 ± 2.1^d (22, 19)	33 ± 1.4 ^d (34, 32)	40.5 ± 6.3 ^d (36,45)	+	40.5 ± 6.3 ^d (36,45) /NR	NR	NR	1/6	Iranian	[26]
Frameshift /Nonsense	c.435_436insAG; p.W146SfsX16^c/ c.862C > T; p.Q288X^c	CH	Lumenal domain / GC binding domain	20	NR	23	NR	23	22–23	20	±	NR	Unilateral ureteropelvic junction	1/1	French Canadian/ Irish English	[27]
Frameshift	c.134delA; p.N45MfsX88	HM	Lumenal domain	18.4 ± 6.7	28 (II.9)	18 ± 8.9	21.4 ± 3.2	19.9 ± 2.6	21.4 ± 2.3	+	28 (II.9)/ +	21 (II.13)	Irritability, impaired executive functions/ attention	1/5	Turkish	Present study

This table indicates the genetic and clinical features of the reported families associated with AMRF. ^aAverage age at onset was indicated, in case of more than one carriers of the same mutation have different ages at onset. In case of only one affected from a family, age at onset of symptoms corresponding to that individual was indicated. When available, age at onsets of all the individuals were indicated in parenthesis. ^bAverage age at death was indicated, in case of more than one carriers of the same mutation have different ages at death. When available, age at deaths of all the individuals were indicated in parenthesis. ^cFounder mutation. ^dThe average age at onsets were indicated based on the clinical information of two reported individuals (IV.9, IV.12). ^eWhen the average age at onsets could not be calculated, only the onsets of the corresponding symptoms for each individual were indicated. ^fThe possibility of second SCARB2 PV. NR: not reported in the corresponding study, -: not observed in the corresponding study, HM homozygote, CH compound heterozygot, H heterozygot, + : observed in the patients but not detailed information provided in the corresponding studies, ?: the correct nomenclature could not be found in the original study

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