Farber lipogranulomatosis (continued), IPDGC ASAH1 LSD variants table, CADD C-Score note, GALC, Genetics GALC for PD

Farber lipogranulomatosis (continued)

cannot break down ceramides properly and they build up in the lysosomes of various cells, including in the lung, liver, colon, muscles used for movement (skeletal muscles), cartilage, and bone. The buildup of ceramides along with the reduction of its fatty breakdown products in cells likely causes the signs and symptoms of Farber lipogranulomatosis. It is unclear whether the level of acid ceramidase activity is related to the severity of the disorder. → Three classic signs occur in Farber lipogranulomatosis: a hoarse voice or a weak cry, small lumps of fat under the skin and in other tissues (lipogranulomas), and swollen and painful joints. Signs and symptoms typically first develop in infancy.

[Robak 2017] In these gene-based analyses, besides the expected result for GBA (P = 0.0001) and confirmation of SMPD1 (P = 0.029), we discover evidence of novel aggregate associations for variants in CTSD (P = 0.002), SLC17A5 (P = 0.005), and ASAH1 (P = 0.031).

IPDGC LSD-Gene-Variants Supplementary Table 3 (ASAH1)

[Supplementary Table 3. LSD Gene Variants in the IPDGC Dataset]

All putative damaging variants (category 2b: MAF<3%, CADD C-Score >12.37) considered among 51 LSD genes are listed. For each variant, CADD C-Score and frequency reported in the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org) browser is noted along with the minor allele frequency (MAF) in IPDGC cases and controls. The final column includes variant annotations of reported pathogenicity for LSDs, based on ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/), as follows: B, benign; LB, likely benign; P, pathogenic; LP, likely pathogenic; CIP, conflicting interpretations of pathogenicity; US, uncertain significance. In several cases, an alternative variant (p.X###Y) is established to be pathogenic at the same position, and this is noted. All other variants without documentation in ClinVar are indicated with a dash (-).

Gene	Position	Variant	Transcript	CADD	EXAC MAF	IPDGC MAF Cases	IPDGC MAF Controls	LSD Pathogenicity (ClinVar)
ASAH1	8:17915087	c.G1192A:p.E398K	NM_004315	32	7.0×10-4		4.4×10-3
	8:17915126	c.G1153A:p.V385I		22.4	1.6×10-3	4.6×10-4	1.2×10-3
ASAH1	8:17916378	c.A1112G:p.Y371C		26.1		4.7×10-4	9.2×10-3
	8:17916861	c.A1078C:p.I360		23.2			1.1×10-3
	8:17916887	c.C1052T:p.T351M	NM_004315	21.1			6.0×10-4
	8:17918934	c.T785C:p.V262A		14.1			0.022
	8:17919807	c.TG677C:p.M226T		19.95			7.4×10-3
	8:17919816	c.A668T:p.Y223F		25.6			1.7×10-3
	8:17921986	c.T485C:p.I162T		25			8.7×10-4
	8:17922029	c.T442G:p.S148A		13.04			4.4×10-4
	8:17924735	c.C424A:p.P142T		28.8			1.5×10-3
	8:17924737	c.T422C:p.J141T		23.4			3.1×10-4
	8:17927315	c.G337C:p.V113I		22			3.1×10-3
ASAH1	8:17927368	c.284_285insACCAATTCCCCAAATTTAAGTCC:p.S95fs		24.4			9.3×10-4
	8:17933087	c.G136A:p.D46N		22.7			9.3×10-3
	8:17942273	c.G38A:p.G13E		23.6			2.5×10-3
	8:17942276	c.G35C:p.R12P					7.7×10-5

Cf) CADD C-Score

Combined Annotation-Dependent Depletion, a tool for scoring the deleteriousness of single nucleotide variants as well as insertion/deletions variants in the human genome. ranges from 1 to 99. A CADD score represents a ranking not a prediction, and no threshold is defined for a specific purpose.

• a scaled C-score of greater of equal 10 indicates that these are predicted to be the 10% most deleterious substitutions that you can do to the human genome
• a score of greater or equal 20 indicates the 1% most deleterious and so on.
• CADD C-score >12.37, representing the top 2% most damaging of all possible nucleotide changes in the genome

CADD scores are based on diverse genomic features derived from surrounding sequence context, gene model annotations, evolutionary constraint, epigenetic measurements and functional predictions. For any given variant, all of these annotations are integrated into a single CADD score via a machine learning model. CADD scores are freely available for all non-commercial applications from the CADD website.

GALC (galactosylceramidase) (=galactocerebrosidase) (=Galcase)

field	content
Function	• removes galactose from ceramide derivatives • Through a process called hydrolysis, this enzyme uses water molecules to break down certain fats called galactolipids
Substrates of GALC	galactosylSph (= psychosine, = globoid cell leukodystrophy) psychosine induces aggregation of a-syn in NSC34 motor-neuron cells (Abdelkarim et al., 2018, PMID: 30127535) galactosylceramide (GalCer) — Galactosylceramide is an important component of myelin
Product of GALC	Sphingosine
Location	lysosome
Note	↓ GALC → ↑ GalCer & psychosine 모두 GALC mutation 환자는 원래 ↑ GalCer 인데, ACi 치료하면 더 증가하겠네. (부작용 없을지?)

Lysosome cartoons

• Lysosome of Gaucher disease: GlcCer → AC → GlcSph ↑ ; Ceramide; GBA ↓ ; Cer → Sph
• Lysosome of Krabbe disease: GalCer → GalSph ↑ ; GALC ↓ → galactosylceramidase

Genetics GALC for PD

dbSNP	level	Frequency	level	activity	Consequence	Clinical reported in ClinVar
rs8005172	potential enhancer region	0.4			as eQTL of GALC in brain, blood, and several cell types, and indicate that GALC is upregulated in PD brain and whole blood and down-regulated in monocyte of PD patients (source?) (Chang, 2017 #2197) and 20220718 NDU Q report: GALC deficiency (who said deficiency?) is a risk factor for PD and leads to the accumulation of GalSph. In recent meta. the effect allele frequency for GALC in PD was 0.42 in PD and OR for risk of PD =~1.05-1.10. (Senkevich 2022) associated with PD in two previous GWAS meta-analyses 1, 18,
rs979812	SNV Intron		hit	may lead to ↓ GALC	(Kia, 2021 #2198) table 2: splicing 가 이상이라는 듯	Not reported
Rs2008686	p.I562T				(Senkevich, 2022 #2174) ↑ (unexpected), (colocalization analysis) ↑ (b=1.2; se=0.06; p=5.10E-95). (Senkevich, 2022 #2174) improper maturation of GalCase affecting activity (Senkevich, 2022 #2174, structural analysis)	None
	p.Phe596Ser	near promoter region
	p.Trp132					O (pathogenic)
rs200960659 This variant is also known	p.Thr112Ala				(Shin, 2016 #2206) fig C&D, fig E&F
	p.Tyr173Leu
	p.Thr529Met
	p.Met117Leu
Deletions

resource: https://databases.lovd.nl/shared/variants/GALC?object_id=VariantOnTranscript%2CVariantOnGenome&id=GALC&order=VariantOnTranscript%2FDNA%2CASC&search_transcriptid=00025233&page_size=1000&page=1

GALC mutation ((likely) pathogenic) → ↓ GALC activity (Marshall, 2018 #2200)

GALC protein → GALC activity → ↑ Psychosine?

PD-genic GALC variant with a substantial effect size (OR) — KD-genic 도 넣던지.

mutations causing severely diminished are listed in bold:

• p.Trp132*

Cause TP / KD?

dbSNP: rs200960659 — This variant is also known.

Uncertain Spans

location	transcription	uncertainty
IPDGC table	column-to-cell alignment for IPDGC MAF Cases and IPDGC MAF Controls	the dense numeric columns are reconstructed from visible OCR; some cell-to-row mappings may need image-level review.
ASAH1 / 8:17916861	c.A1078C:p.I360	reads as written; the variant code is partially clipped at the right edge.