Case#: Xin_Patient_5, sex not mentioned, age 17 at onset, U.S. nationality, admixed European non-Finnish ethnicity

CasePresentingHPOs: HP:0004302 (Functional motor deficit), HP:0000572 (Visual loss), HP:0001250 (Seizure), HP:0001268 (Mental deterioration), HP:0003581 (Adult onset), HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material)

CaseHPOFreeText: Motor difficulty was the phenotype at presentation (age 17). Visual loss (age 18), Cognitive regression (age 25), and seizure (age 18) subsequently developed. Granular type inclusions were observed in blood by electron microscopy. Fingerprint inclusions were observed in the brain.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing for mutations in the CLN1, CLN2, CLN3, CLN6, and CLN8 had already occurred, using PCR amplification and Sanger sequencing to exclude the possibility of variants in the exons and surrounding noncoding regions. Genome-wide analysis methods were not used, as NCL had already been diagnosed based on clinical phenotypes.

CaseMethod1: PCR amplification of the coding and surrounding non-coding regions of each gene, followed by bidirectional Sanger sequencing.

CaseMethod2: as mentioned

CaseGenotypingMethod: CLN5 genotyping was performed by PCR amplification of the four exons and surrounding non-coding regions was performed, followed by bi-directional Sanger sequencing. Synthetic multiplex ligation-dependent probe amplification (MLPA) was then used to calculate average gene dosage ratio for each ratio, in order to detect large deletions.

Variant: The patient harbors the NM_006493.4(CLN5):c.974A>G (p.Tyr325Cys) variant as well as a chromosomal deletion that includes exon 4.

ClinVar: 2570 (in trans with exon 4 deletion with undefined boundaries)

gnomAD: Maximum allele frequency for NM_006493.4(CLN5):c.974A>G (p.Tyr325Cys) is 0.00002784 (in the European non-Finnish population, no homozygotes). https://gnomad.broadinstitute.org/variant/13-77575001-A-G

VariantEvidence: The variant encodes a missense substitution that adds a cysteine to the CLN5 protein and may disrupt its structure. In a previous publication from an overlapping group of authors, mass spectrometry confirmed absence of CLN5 protein expression in samples from an individual harboring this variant, but in not control samples (PMID:19383612).

CaseAddInfo: Although parents do not appear to have been genotyped, the missense variant (in exon 4) can be inferred to be in trans with the exon 4 deletion.

CasePMIDs: N/A

Case#: Xin_Patient_3, sex not mentioned, age 17 at onset, U.S. nationality, admixed European non-Finnish ethnicity

CasePresentingHPOs: HP:0004302 (Functional motor deficit), HP:0000572 (Visual loss), HP:0001250 (Seizure), HP:0001268 (Mental deterioration), HP:0003581 (Adult onset), HP:0003205 (Curvilinear intracellular accumulation of autofluorescent lipopigment storage material), HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material), HP:0003226 (Rectilinear intracellular accumulation of autofluorescent lipopigment storage material)

CaseHPOFreeText: Cognitive regression was the phenotype at presentation (age 17). Visual loss (age 20), motor difficulty (age 23), and seizure (age 23) subsequently developed. Granular type inclusions were observed by electron microscopy. Fingerprint inclusions were observed in the skin, rectilinear inclusions were observed in the muscle, and curvilinear inclusions were observed in neurons, glial cells, muscle, and spleen.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing for mutations in the CLN1, CLN2, CLN3, CLN6, and CLN8 had already occurred, using PCR amplification and Sanger sequencing to exclude the possibility of variants in the exons and surrounding noncoding regions. Genome-wide analysis methods were not used, as NCL had already been diagnosed based on clinical phenotypes.

CaseMethod1: PCR amplification of the coding and surrounding non-coding regions of each gene, followed by bidirectional Sanger sequencing

CaseMethod2: as mentioned

CaseGenotypingMethod: CLN5 genotyping was performed by PCR amplification of the four exons and surrounding non-coding regions was performed, followed by bi-directional Sanger sequencing. Synthetic multiplex ligation-dependent probe amplification (MLPA) was then used to calculate average gene dosage ratio for each ratio, in order to detect large deletions.

Variant: The patient harbors the NM_006493.4(CLN5):c.230G>A (p.Cys77Tyr) and NM_006493.4(CLN5):c.974A>G (p.Tyr325Cys) variants.

ClinVar: 2569, 2570

gnomAD: The NM_006493.4(CLN5):c.230G>A (p.Cys77Tyr) variant is not found in gnomAD. Maximum allele frequency for NM_006493.4(CLN5):c.974A>G (p.Tyr325Cys) is 0.00002784 (in the European non-Finnish population, no homozygotes). https://gnomad.broadinstitute.org/variant/13-77575001-A-G

VariantEvidence: Both variants encode missense substitutions in the protein product. Because both change the total number of cysteines in the CLN5 protein, they may disrupt its structure. In a previous publication from an overlapping group of authors, mass spectrometry confirmed absence of CLN5 protein expression in samples from this individual, but in not control samples (PMID:19383612).

CaseAddInfo: Parents do not appear to have been genotyped, so it is not clear whether the two variants are confirmed to be in trans.

CasePMIDs: 19383612

PMID: 20157158

Gene: CLN5

HGNC: 2076

Disease: Ceroid lipofuscinosis, neuronal, 5 (also known as Finnish variant late infantile neuronal ceroid lipofuscinosis, neuronal ceroid lipofuscinosis late infantile Finnish variant, or Finnish vLINCL)

MONDO: 0009745

InheritancePattern: Autosomal Recessive

Prevalence: Unknown, but part of a larger group of NCL disorders with a collective prevalence between 1 in 12,500 (PMID:9662406) and 1 in 100,000 (PMID:23374165)

Penetrance: Fully penetrant, with onset often in the late infantile period but in some cases during early adulthood or even as late as in the 6th decade of life

Case#: Xin_Patient_6, sex not mentioned, age 8 at onset, Swedish nationality

CasePresentingHPOs: HP:0004302 (Functional motor deficit), HP:0000572 (Visual loss), HP:0001250 (Seizure), HP:0001268 (Mental deterioration), HP:0003621 (Juvenile onset), HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material), HP:0003205 (Curvilinear intracellular accumulation of autofluorescent lipopigment storage material)

CaseHPOFreeText: Motor difficulty was the phenotype at presentation (age 8). Seizures (age 8), Visual loss (age 12), and Cognitive regression (age 11) subsequently developed. Curvilinear inclusions were observed in the skin specifically.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing for mutations in the CLN1, CLN2, CLN3, CLN6, and CLN8 had already occurred, using PCR amplification and Sanger sequencing to exclude the possibility of variants in the exons and surrounding noncoding regions. Genome-wide analysis methods were not used, as NCL had already been diagnosed based on clinical phenotypes.

CaseMethod1: PCR amplification of the coding and surrounding non-coding regions of each gene, followed by bidirectional Sanger sequencing.

CaseMethod2: as mentioned

CaseGenotypingMethod: CLN5 genotyping was performed by PCR amplification of the four exons and surrounding non-coding regions was performed, followed by bi-directional Sanger sequencing. Synthetic multiplex ligation-dependent probe amplification (MLPA) was then used to calculate average gene dosage ratio for each ratio, in order to detect large deletions.

Variant: The patient harbors the NM_006493.4(CLN5):c.78G>A (p.Trp26Ter) and NM_006493.4(CLN5):c.522dup (p.Trp175LeufsTer30) variants, as well as the likely benign NM_006493.4(CLN5):c.381T>G (p.Thr127=) variant.

ClinVar: 2565, 56543, 128783

gnomAD: Maximum allele frequency for NM_006493.4(CLN5):c.78G>A (p.Trp26Ter) is 0.00005132 (in the European non-Finnish population, no homozygotes). https://gnomad.broadinstitute.org/variant/13-77566311-G-A Maximum allele frequency for NM_006493.4(CLN5):c.522dup (p.Trp175fs) is 0.00007033 (in the European non-Finnish population, no homozygotes). Maximum allele frequency for the NM_006493.4(CLN5):c.381T>G (p.Thr127=) variant is 0.06570 (in the East Asian population, 48 homozygotes) https://gnomad.broadinstitute.org/variant/13-77570078-T-G

VariantEvidence: The NM_006493.4(CLN5):c.78G>A (p.Trp26Ter) nonsense variant is likely to be subject to nonsense mediated decay. The NM_006493.4(CLN5):c.522dup (p.Trp175fs) frameshift variant is predicted to truncate ~51% of the protein. On the other hand, the synonymous NM_006493.4(CLN5):c.381T>G (p.Thr127=) variant appears unlikely to have a gene impact.

CaseAddInfo: Parents do not appear to have been genotyped, so it is unclear whether the two variants with predicted gene impact have been shown or simply assumed to be in trans. The same is true for the benign, synonymous variant.

CasePMIDs: N/A

PMID: 19309691

Gene: CLN5

HGNC: 2076

Disease: Ceroid lipofuscinosis, neuronal, 5 (also known as Finnish variant late infantile neuronal ceroid lipofuscinosis, neuronal ceroid lipofuscinosis late infantile Finnish variant, or Finnish vLINCL)

MONDO: 0009745

InheritancePattern: Autosomal Recessive

Prevalence: Unknown, but part of a larger group of NCL disorders with a collective prevalence between 1 in 12,500 (PMID:9662406) and 1 in 100,000 (PMID:23374165)

Penetrance: Fully penetrant, with onset often in the late infantile period but in some cases during early adulthood or even as late as in the 6th decade of life

FamilyLabel: Lebrun_2009_Family_1

Family#PresentingHPOs: HP:0001251 (Ataxia), HP:0001250 (Seizure), HP:0002463 (Language impairment), HP:0011463 (Childhood onset),

Family#PresentingHPOFreeText: Abnormalities on brain MRI scan

FamilyNotHPOs: N/A

FamilyNotHPOFreeText: N/A

CountryOrigin: United Kingdom

Ethnicity: Family is of Pakistani ethnic origin.

Race: N/A

Family#PreviousTesting: Genome-wide methods were not initially used, as clinical phenotypes were consistent with diagnosis of neuronal ceroid lipofuscinosis (NCL). Enzymatic tests ruled out defects in the CLN1, CLN2, and CLN10 loci, while CLN3, CLN6, and CLN8 defects were ruled out by Sanger sequencing of the coding regions. SNP array-based homozygosity mapping was performed, revealing 7 homozygous candidate regions in the affected members from the (consanguineous) family. These regions were analyzed for candidate NCL genes, finding CLN5 as the most likely locus to harbor the causative variant.

Family#Method1: SNP array-based homozygosity mapping was performed, revealing 7 homozygous candidate regions in the affected members from the (consanguineous) family. These regions were analyzed for candidate NCL genes, finding CLN5 as the most likely candidate for further genotyping.

Family#Method2: N/A

Family#GenotypingMethod: CLN5 mRNA was reverse transcribed, PCR-amplified, and subjected to Sanger sequencing. This process was performed for both affected and control individuals (parents and unaffected sibling).

Affected: 2

Unaffected: 1

Segregations: 1 segregation is reported in the family.

PublishedLOD: N/A

eLOD: N/A

AddSegregationInfo: N/A

ProbandLabel: Lebrun_2009_Patient_1

Variant: Both affected patients are homozygous for NM_006493.4(CLN5):c.924_925del (p.Leu309fs), (although this variant is referred to in the article as c.1072_1073delTT (p.Leu358AlafsX4)).

ClinVar: 56526

gnomAD: The variant is reported to have a maximum allele frequency of 0.0002603 (in the Latino / Admixed American population, with no homozygous individuals). https://gnomad.broadinstitute.org/variant/13-77574801-AAT-A

FamilyAddInfo: The family has some degree of consanguinity, as parents are described as distantly related. Parents were heterozygous for the variant. Family relationships between individuals were verified.

FamilyPMIDs: N/A

PMID: 25359263

Gene: CLN5

HGNC: 2076

Disease: Ceroid lipofuscinosis, neuronal, 5 (also known as Finnish variant late infantile neuronal ceroid lipofuscinosis, neuronal ceroid lipofuscinosis late infantile Finnish variant, or Finnish vLINCL)

MONDO: 0009745

InheritancePattern: Autosomal Recessive

Prevalence: Unknown, but part of a larger group of NCL disorders with a collective prevalence between 1 in 12,500 (PMID:9662406) and 1 in 100,000 (PMID:23374165)

Penetrance: Fully penetrant, with onset often in the late infantile period but in some cases during early adulthood or even as late as in the 6th decade of life

Case#: Pineda-Trujillo_Patient_NCL-22, male, age 9 at onset and age 14 at death, Colombian origin with family ethnicity reported as an admixture of Spanish, Native American, and African ancestry

CasePresentingHPOs: HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material), HP:0003621 (Juvenile onset), HP:0000572 (Visual loss), HP:0003678 (Rapidly progressive), HP:0011421 (Death in adolescence), HP:0025406 (Asthenia), HP:0200085 (Limb tremor), HP:0000618 (Blindness), HP:0002540 (Inability to walk), HP:0000708 (Behavioral abnormality), HP:0007064 (Progressive language deterioration), HP:0001336 (Myoclonus), HP:0001250 (Seizure), HP:0002120 (Cerebral cortical atrophy), HP:0001272 (Cerebellar atrophy), HP:0002392 (EEG with polyspike wave complexes)

CaseHPOFreeText: Onset was at age 9, with the first presenting phenotype being visual failure rather than mental retardation. Electron microscopy of skin biopsies found inclusions consisting of fingerprint profiles, which were often condensed and sometimes associated with lipid droplets. Tremor was observed in lower limbs. Blindness and inability to walk developed at approximately age 10 (within a year of symptom onset). Behavioral changes, gradual loss of language, myoclonus, and seizures all occurred within months of onset. Seizures were poorly responsive to valproate or clonazepam. Generalized cortical and cerebellar atrophy without signal intensity changes were seen by NMR at CT scans at age 12. EEG specifically showed a generalized pattern of high-voltage polyspike–slow waves. Patient died at age 14.

CaseNotHPOs: HP:0003205 (Curvilinear intracellular accumulation of autofluorescent lipopigment storage material), HP:0003226 (Rectilinear intracellular accumulation of autofluorescent lipopigment storage material), HP:0001922 (Vacuolated lymphocytes), HP:0003457 (EMG abnormality), HP:0100285 (EMG: impaired neuromuscular transmission)

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing relied on clinical testing to establish neuronal ceroid lipofuscinosis (CLN), then used 10 different microsatellite markers to evaluate the 6 loci known at the time to be associated with CLN. (Note: This list of CLN-associated loci has since expanded from 6 to 8-12 genes.) The pedigree indicates consistent segregation of the disease phenotype with biallelic inheritance of the three markers in the CLN5 locus. CLN genes were then PCR-amplified and subjected to Sanger sequencing, identifying a variant in CLN5. Genome-wide analysis methods were not used.

CaseMethod1: Linkage analysis with 10 microsatellite markers across 6 candidate loci known to be associated with CLN phenotypes.

CaseMethod2: CLN genes (specifically CLN3 and CLN5) were PCR-amplified and subjected to Sanger sequencing, identifying a variant in CLN5.

CaseGenotypingMethod: CLN5 PCR products were subjected to PshAI endonuclease digestion, as the variant abolishes a restriction site. Genome-wide analysis methods were not used.

Variant: Patient was homozygous for NM_006493.4(CLN5):c.188G>A (p.Arg63His), (although this variant is referred to in the article as c.1627G>A or p.Arg112His).

ClinVar: 2567

gnomAD: The variant is reported to have a maximum allele frequency of 0.00003274 (in the South Asian population, with no homozygous individuals). https://gnomad.broadinstitute.org/variant/13-77569212-G-A

VariantEvidence: The variant encodes a missense substitution, and exhibits defective localization to the ER rather than the lysosome (PMID:20052765).

CaseAddInfo: N/A

CasePMIDs: N/A

PMID: 22431521

Gene: CLN5

HGNC: 2076

Disease: Ceroid lipofuscinosis, neuronal, 5 (also known as Finnish variant late infantile neuronal ceroid lipofuscinosis, neuronal ceroid lipofuscinosis late infantile Finnish variant, or Finnish vLINCL)

MONDO: 0009745

InheritancePattern: Autosomal Recessive

Prevalence: Unknown, but part of a larger group of NCL disorders with a collective prevalence between 1 in 12,500 (PMID:9662406) and 1 in 100,000 (PMID:23374165)

Penetrance: Fully penetrant, with onset often in the late infantile period but in some cases during early adulthood or even as late as in the 6th decade of life

ExperimentName: Mouse model of homozygous Cln5 loss

NonHumanModel: Mus musculus

GeneAlteration: Mice are homozygous for Cln5 loss of function, caused by Insertion of a neomycin resistance cassette eliminating exon 3, resulting in a premature stop codon in exon 4. The presence or absence of a truncated gene product was not assessed.

ModelPhenotype: HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material), HP:0003205 (Curvilinear intracellular accumulation of autofluorescent lipopigment storage material), HP:0000572 (Visual loss)

HumanPhenotype: HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material), HP:0003205 (Curvilinear intracellular accumulation of autofluorescent lipopigment storage material), HP:0000572 (Visual loss)

ModelEvidence: The model phenotypes closely match the human patient phenotypes at the microscopic level (characteristic autofluorescent inclusion bodies ) as well as the loss of vision, but do not reproduce neurological features such as seizures, ataxia, loss of motor coordination, mental regression, and behavioral changes.

ModelVariant: While it is unclear whether the mice express a truncated form of Cln5 or whether this form is degraded, the predicted protein product does not represent a particular human variant. The authors speculate that it may be most similar to the NM_006493.4(CLN5):c.522dup (p.Trp175LeufsTer30) variant (PMID:10953198).

Case#: Bessa_Patient_1, female, age 3 at onset, Portuguese nationality

CasePresentingHPOs: HP:0000736 (Short attention span), HP:0002463 (Language impairment), HP:0002312 (Clumsiness), HP:0033044 (Motor regression), HP:0002376 (Developmental regression), HP:0000572 (Visual loss), HP:0002066 (Gait ataxia), HP:0001336 (Myoclonus), HP:0010819 (Atonic seizure), HP:0032794 (Myoclonic HP:0000648 (Optic atrophy), HP:0000546 (Retinal degeneration), HP:0012011 (EEG with occipital focal spike waves), HP:0002059 (Cerebral atrophy), HP:0001272 (Cerebellar atrophy), HP:0030891 (Periventricular white matter hyperdensities), HP:0001268 (Mental deterioration), HP:0031058 (Impairment of activities of daily living), HP:0011463 (Childhood onset), HP:0000712 (Emotional lability), HP:0002015 (Dysphagia), HP:0010864 (Intellectual disability, severe), HP:0001332 (Dystonia), HP:0007256 HP:0025357 (Erratic myoclonus), HP:0003205 (Curvilinear intracellular accumulation of autofluorescent lipopigment storage material), HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material)

CaseHPOFreeText: Progressive attention deficits and regression of language ability were the phenotypes at presentation (age 3). Motor clumsiness presented at age 4, initiating a larger pattern of developmental regression. Phenotypes with onset at age 7 included visual deterioration, gait ataxia, distal and axial myoclonus, atonic and myoclonic generalized epileptic seizures, bilateral optic atrophy, retinal degeneration, abnormal EEG showing diffuse slowing of background rhythm and occipital spike-wave activity, and abnormal brain MRI with cerebral and cerebellar atrophy as well as increased signal intensity of both the posterior limb of the capsula interna and the periventricular white matter. At age 8, any independence in daily activities was lost, as well as any language abilities. Ataxic gait was marked, and EEG activity showed slowing and disorganization, frequent multifocal high-voltage polyspike-slow wave complexes, and epileptic activity corresponding to myoclonus. At 15 years (time of study), the patient was bedridden and showed amaurotic behavior, emotional lability, marked dysphagia, severe mental retardation, dystonic postures of the limbs and trunk, pyramidal signs in the limbs, bilateral optic atrophy, and frequent myoclonus (both erratic and stimulus-induced). Intracellular accumulation of autofluorescent lipopigment storage material was also detected at age 15.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotype testing was not performed. While the PPT1 and TPP1 loci were not sequenced, their enzymatic activity in extracts from leucocyte and fibroblast cells was confirmed to be within the normal range.

CaseGenotypingMethod: Based on detailed clinical phenotypes consistent with variant NCL with late-infantile onset, coding regions and intron boundaries of the CLN3, CLN5, and CLN6 loci were PCR-amplified and subjected to Sanger sequencing. Genome-wide analysis methods were not used. Parents (and patient) were subsequently genotyped using single strand conformational polymorphisms and restriction digest of PCR products, to identify variants in cis and in trans with one another.

Variant: The patient is a compound heterozygote with a paternally inherited NM_006493.4(CLN5):c.418C>T (p.Gln140Ter) variant and maternally inherited NM_006493.4(CLN5):c.688G>A (p.Asp230Asn) and NM_006493.4(CLN5):c.188G>C (p.Arg63Pro) variants.

ClinVar: 56538, 2566, 56533

gnomAD: The maximum allele frequency of the NM_006493.4(CLN5):c.688G>A (p.Asp230Asn) variant is 0.00005437 (within the East Asian population, with no homozygous occurrences). https://gnomad.broadinstitute.org/variant/13-77574715-G-A The NM_006493.4(CLN5):c.418C>T (p.Gln140Ter) and NM_006493.4(CLN5):c.188G>C (p.Arg63Pro) variants are absent from gnomAD.

VariantEvidence: Reduced CLN5 expression by 45% at the mRNA level indicates that one of the two alleles may be subject to nonsense mediated decay and likely absence of the corresponding protein product. This may confirm the prediction that the nonsense variant NM_006493.4(CLN5):c.418C>T (p.Gln140Ter) is likely subject to nonsense mediated decay. One of the two maternally inherited variants, NM_006493.4(CLN5):c.688G>A (p.Asp230Asn), has been previously shown to introduce an additional N-glycosylation site within the C-terminal region of CLN5 (PMID:20052765) and to disturb its localization to the lysosome (PMID:20052765).

CaseAddInfo: Parents are healthy and non-consanguineous.

CasePMIDs: N/A

ExperimentName: Interaction with TPP1 and CLN3

InteractingGene: TPP1 (formerly known as CLN2) and CLN3

InteractionType: Physical (protein-protein) interaction

InteractionMethod: Co-immunoprecipitation

InteractionEvidence: PPT1 (aka CLN1), CLN3, and CLN5 were exogenously expressed in COS-1 cells. Immunoprecipitation of endogenous TPP1 (Fig. 5A) or exogenously expressed CLN3 (Fig. 5B) successfully co-immunoprecipitated CLN5 (demonstrated by western blotting). Immunoprecipitation of GST-CLN5 successfully co-immunoprecipitated TPP1 and CLN3 (Fig. 5C). This evidence helps validate the link between CLN5 variants and neuronal ceroid lipofuscinosis, as both TPP1 and CLN3 have also been linked with this disease state.

Case#: Savukoski_Fin_Minor_Patient_1, no demographic details, Finnish origin

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous testing relied on linkage analysis using PCR-amplifiable polymorphisms, including microsatellite markers. The marker D13S160 was found to co-segregate with disease with a LOD score of 4.78 across 14 Finnish pedigrees, mapping the disease locus to chromosome 13q21.1-q32 (PMID:7942847). A follow-up study used two additional microsatellite markers to map the locus to a 200-kb region (PMID:8661106), which was then analyzed in the present study and found to contain a single coding gene.

CaseMethod1: Linkage analysis using PCR-amplifiable polymorphisms, including microsatellite markers, followed by more detailed linkage analysis using two additional microsatellite markers to map the locus to a smaller 200-kb region (PMID:8661106).

CaseMethod2: N/A

CaseGenotypingMethod: PCR products from the four exons of CLN5 were generated from the affected individual and a control individual and subjected to Sanger sequencing. Genome-wide analysis methods were not used.

Variant: Patient is homozygous for NM_006493.4(CLN5):c.78G>A (p.Trp26Ter), although this variant is referred to in the article as c.G1517A or p.Trp75Stop.

ClinVar: 2565

gnomAD: The variant is reported to have a maximum allele frequency of 0.00005132 (in the European non-Finnish population, with no homozygous individuals). https://gnomad.broadinstitute.org/variant/13-77566311-G-A

VariantEvidence: This nonsense variant is predicted to introduce a stop codon near the N-terminus of the encoded protein, likely triggering NMD and the absence of a protein product (loss of function).

CaseAddInfo: N/A

CasePMIDs: PMID:7942847, PMID:8661106