Portugal ARJP Table And Parkin Review Evidence

9 different deletions either in homozygosity or heterozygosity.

• The most common deletions were those of exon 4 and of exons 3-6 (table 1)

Js: from the below table, 21 patients had a family history, so half!

Table 1. Portugal ARJP Molecular Diagnosis

Table 1. Overview of molecular and clinical information from 40 patients with a molecular diagnosis of autosomal recessive juvenile Parkinson disease

Patient	Age at onset, y	cDNA	Protein	Family history	Consanguinity
1	22	c.1244C>A + c.172-52958_734+8943del	[p.T415N] + [p.?]	Yes	No
2	28	c.171+67708_734+58232delins28 + c.171+67708_734+58232delins28	[p.?] + [p.?]	No	No
3	38	c.155delA + c.155delA	[p.N52Mfs*29] + [p.N52Mfs*29]	No	Yes
4	25	c.155delA + c.155delA	[p.N52Mfs*29] + [p.N52Mfs*29]	Yes	No
5	17	c.413-18966_871+72957delinsA + c.413-18966_871+72957delinsA	[p.?] + [p.?]	No	Yes
6	32	c.155delA + c.155delA	[p.N52Mfs*29] + [p.N52Mfs*29]	Yes	Yes
7	30	c.155delA + c.155delA	[p.N52Mfs*29] + [p.N52Mfs*29]	No	No
8	27	c.155delA + c.155delA	[p.N52Mfs*29] + [p.N52Mfs*29]	No	No
9	13	c.155delA + c.823C>T	[p.N52Mfs*29] + [p.R275W]	Yes	No
10	31	c.125G>C + c.8-51491_172-56018del	[p.R42P] + [p.?]	No	No
11	35	c.155delA + c.155delA	[p.N52Mfs*29] + [p.N52Mfs*29]	No	No
12	25	c.155delA + c.155delA	[p.N52Mfs*29] + [p.N52Mfs*29]	Yes	No
13	28	c.155delA + c.172-11910_413-22473del	[p.N52Mfs*29] + [p.?]	No	No
15	17	c.823C>T + c.823C>T	[p.R275W] + [p.R275W]	Yes	No
16	10	c.1072_1073delinsA + c.1072_1073delinsA	[p.L358Rfs*77] + [p.L358Rfs*77]	No	No
17	17	c.171+67708_734+58232delins28 + c.171+67708_734+58232delins28	[p.?] + [p.?]	Yes	No
18	35	c.155delA + c.155delA	[p.N52Mfs*29] + [p.N52Mfs*29]	Yes	No
19	27	c.155delA + c.155delA	[p.N52Mfs*29] + [p.N52Mfs*29]	Yes	No
20	34	c.1084-3859_1167+1618del + c.1084-3859_1167+1618del	[p.?] + [p.?]	No	Yes
21	23	c.155delA + c.735-21670_1083+48265delinsATG	[p.N52Mfs*29] + [p.?]	Yes	No
22	51	c.823C>T + c.413-16409_534+27042delinsATGCCTGTAA	[p.R275W] + [p.?]	No	No
23	18	c.155delA + c.155delA	[p.N52Mfs*29] + [p.N52Mfs*29]	Yes	No
24	30	c.155delA + c.823204_172-3140del	[p.N52Mfs*29] + [p.?]	Yes	No
25	24	c.413-3460_534+30928del + c.413-3460_534+30928del	[p.?] + [p.?]	No	Yes
26	-	c.155delA + c.155delA	[p.N52Mfs*29] + [p.N52Mfs*29]	Yes	No
27	42	c.155delA + c.155delA	[p.N52Mfs*29] + [p.N52Mfs*29]	No	No
28	12	c.155delA + c.155delA	[p.N52Mfs*29] + [p.N52Mfs*29]	Yes	No
29	33	c.125G>C + c.125G>C	[p.R42P] + [p.R42P]	No	No
30	39	c.155delA + c.412+25822_535-71707delinsTGA	[p.N52Mfs*29] + [p.?]	No	No
31	50	c.155delA + c.172-16570_734+51279del	[p.N52Mfs*29] + [p.?]	Yes	No
32	13	c.155delA + c.823C>T	[p.N52Mfs*29] + [p.R275W]	Yes	No
33	38	c.413-27055_534+20428del + c.413-27055_534+20428del	[p.?] + [p.?]	No	No
34	52	c.155delA + c.155delA	[p.N52Mfs*29] + [p.N52Mfs*29]	Yes	Yes
38	55	c.1097G>A + c.413-10504_534+408delins20	[p.R366Q] + [p.?]	No	No
39	34	c.1030delG + c.1286-3C>G	[p.E344Sfs*91] + [p.?]	No	No
40	44	c.155delA + c.412+2768_734+82226del	[p.N52Mfs*29] + [p.?]	Yes	No

Klein, 2012 #915 Review

Parkin | PINK1 | DJ1

887 exonic mutations have been described to date, comprising 147 different changes.

• About a third (293/887) of all exonic mutations are single-nucleotide changes,
• 13% (119/887) are small deletions, and
• 54% (475/887) are deletions or duplications of one or several exons (A Grunewald and C Klein, in prep.)

A deletion of exon 3 is the most frequent mutation in the Parkin gene (88/887, reported in 17 different studies). The second most common change is the c.924C>T (this is DNA level nomenclature, coding region, substitution) single-nucleotide mutation in exon 7 (RING1), which was detected 75 times in 13 different screens (A Grunewald and C Klein, in prep.).

• without dementia.36,41 {Aasly, 2020 #781}

Demographics (these are what we expect for our clinical trials)

• {Kasten, 2018 #708} Supplementary Table 4. Comparison of most frequently considered clinical features in review articles vs. MDSGene data
• https://www.mdsgene.org/d/1/g/4

Akhit, 2016 #1061

Below two SNPs decrease Parkin protein stability, & structure & ↓ function (evidence내가 아직 못 발견)

• rs55961220 C289G
• rs56092260 R366W

Darvish, 2013 #1349, Iran

Table 1. Mutations identified in patients with sporadic early-onset PD.

Gene	Zygosity	Mutation	Number of patients	AAO (years)	Ethnicity	Clinical features
Parkin	Homozygous	Deletion of exon 2	5	25-28-31-30-26	Mazandrani	All five patients had typical clinical features
Parkin	Homozygous	Deletion of exon 3	3	22-18-29	Sistani, Azeri, Fars	All three patients had typical clinical features
Parkin	Compound heterozygous	Deletion of exons 2, 3 and 4 + Deletion of exon 3	1	28	Gilaki	Typical clinical features
Parkin	Compound heterozygous	Deletion of exons 2, 3, 4, and 5 + deletion of exons 2, 3 and 4	1	20	Fars	Typical clinical features
Parkin	Compound heterozygous	Deletion of exon 2 + deletion of exons 2 and 3	1	16	Azeri	Typical clinical features
Parkin	Compound heterozygous	Deletion of exon 2 + deletion of exons 2, 3, and 4	1	25	Balochi	Typical clinical features
Parkin	Compound heterozygous	Whole-gene duplication / Whole-gene Triplication	1 / 1	38 / 26	Fars	Typical clinical features / PD + Dementia

Table 2. Mutations identified in patients with familial PD.

Gene	Zygosity	Mutation	Number of families	Number of affected individuals	Mean AAO (years)	Ethnicity	Clinical features
Parkin	Homozygous	Deletion of exon 3	2	2-2	21-31	Mazandrani, Fars	Affected individuals in one of families had PD + Dystonia
Parkin	Homozygous	Deletion of exons 2-12	1	2	18	Lorestani	PD + Dementia
Parkin	Homozygous	Deletion of exon 2	4	3-2-2-2	29-31-30-28	Mazandrani	All affected individuals from four families had typical clinical features
Parkin	Homozygous	Deletion of exons 3, 4, and 5	1	3	25	Mazandrani	All three affected individuals had typical clinical features
Parkin	Compound heterozygous	Deletion of exons 2 and 3 + deletion of exons 2,3, and 4	1	3	29	Fars	All three affected individuals had typical clinical features
Parkin	Compound heterozygous	Deletion of exon 2 + deletion of exons 2 and 3	1	4	30	Fars	All four affected individuals had typical clinical features
Parkin	Compound heterozygous	Deletion of exon 2 + deletion of exons 2,3, and 4	1	2	14	Fars	All two affected individuals had typical clinical features
Parkin	Homozygous	Deletion of exon 5	1	3	42	Fars	All three affected individuals had typical clinical features
Parkin	Homozygous	Deletion of exon 4	1	3	38	Balochi	All three affected individuals had PD + Dementia
[uncertain]	Homozygous	Deletion of exon 2	1	3	12	Torkaman	Kufor-Rakeb syndrome
[uncertain]	[uncertain]	Whole-gene duplication	2	2-2	39-44	Gilaki, Fars	All affected individuals had typical clinical features
[uncertain]	[uncertain]	Whole-gene Triplication	1	3	25	Azeri	All three affected individuals had PD + Dementia

Uncertain Spans

• Portugal Table 1 rows 14, 36, and 37 are not clearly visible in this crop; rows visible enough to transcribe are retained and missing rows are not inferred.
• Several long cDNA deletion strings in Portugal Table 1 are small and may contain punctuation or coordinate errors.
• Klein 2012 review table is preserved as an image asset; only surrounding notes and highlighted aggregate statements are transcribed.
• Darvish 2013 table gene labels at the far left are partly cropped; uncertain rows keep [uncertain] rather than inferred gene names.
• The bottom transition into the following Results section is visible but not enough text is exposed to transcribe beyond the table region.