PMID: 28851564

Gene: RAB39B

Disease: early-onset parkinsonism-intellectual disability syndrome

MonDO: MONDO:0010709

PMID: 28851564

Gene: RAB39B

Disease: early-onset parkinsonism-intellectual disability syndrome

MonDO: MONDO:0010709

Shi, 2016 - A novel RAB39B gene mutation in X-linked juvenile parkinsonism with basal ganglia calcification

PMID: 27943471

Gene: RAB39B

Disease: early-onset parkinsonism-intellectual disability syndrome

MonDO: MONDO:0010709

Shi, 2016 - A novel RAB39B gene mutation in X-linked juvenile parkinsonism with basal ganglia calcification

PMID: 27943471

Gene: RAB39B

Disease: early-onset parkinsonism-intellectual disability syndrome

MonDO: MONDO:0010709

Case#: Wilson_Australian kindred_Person II:2

Demographics: Male, 44y at diagnosis, Australia

CasePresentingHPOs: HP:0000750, HP:0001249, HP:0007351, HP:0002362, HP:0002067, HP:0100660, HP:0002396, HP:0000256

Age at onset <2y, while age at tremor onset was 38y. Birth and early milestones were normal. Early learning difficulties were reported and the proband was able to read and write. Parkinsonism classification was akinetic-rigid. Proband showed L-Dopa response, hypokinetic dysarthria, and normal cerebellar function. Other normal features included normal eye examination, MRI, Fragile X testing, karyotype, Copper testing, blood count and chemistry, urine metabolic testing and hearing.

CaseNotHPOs:

CasePreviousTesting: Linkage analysis using homozygous recessive model identified no linkage to autosomes, but to two regions: Xp22.2 and Xq27.3–qter

CaseMethod1: Copy number variation analysis

CaseMethod2: PCR

CaseGenotypingMethod: A ~45-kb deletion within the Xq haplotype was identified that encompassed the complete RAB39B gene and the last 3 coding exons of CLIC2.

Variant: NC_000023.11:g.(155246216_?)_(?_155288781)del

ClinVar: 157665

CAID:

gnomAD:

VariantEvidence: The proband was hemizygous for the ~45-kb deletion encompassing the complete RAB39B and partial CLIC2 genes. Expression of both transcripts was absent from fibroblast cells of affected individuals. The proband is not scored any points as the variant involves deletion of part of an additional gene, CLIC2. Although the authors ruled out seizures and cardiac anomalies (phenotypes associated with CLIC2 missense variant) in patients from the family, it is not conclusive that CLIC2 deletion does not have any impact on the proband's phenotype.

CaseAddInfo: The proband's siblings were also similarly affected. Elder brother of the proband died at 48y from positional asphyxia, and postmortem neuropathological studies on proband's brain showed pallor of the substantia nigra and locus coeruleus. H&E staining of substantia nigra revealed PD features, including loss of pigmented neurons and Lewy bodies in surviving neurons. Abundance of cortical Lewy bodies, were noted. Tau-immunoreactive NFTs were also observed in a small proportion of the surviving pigmented SN neurons

CasePMIDs:

Wilson_Wisconsin kindred

Family#PresentingHPOs: HP:0001263, HP:0000750, HP:0001249, HP:0002174, HP:0007351, HP:0002362, HP:0002067, HP:0002396, HP:0001260, HP:0000256, HP:0002007, HP:0000218, HP:0001355,

Age at clinical evaluation <2y; early learning difficulty with ability to read and live independently (in some members), age at tremor onset 10-20y, age at Parkinson diagnosis 20s, absent response to L-Dopa, hypokinetic dysarthria, skin depigmented papules, normal cerebellar function and eye examination, normal karyotype, normal copper testing, normal blood count and chemistry, normal urine metabolic testing, normal hearing.

FamilyNotHPOs:

Fragile X syndrome,

CountryOrigin: Germany

Ethnicity:

Race:

Family#PreviousTesting: Multipoint linkage analysis was performed. X chromosome exome sequencing revealed no other variants in the linkage region. Direct sequencing of CLIC2 ruled out variants in the gene.

Family#Method1: Sanger seq

Family#Method2:

Family#GenotypingMethod: RAB39B was directly sequenced

Affected: 16

Unaffected:

Segregations:

PublishedLOD: 6.75

eLOD:

AddSegregationInfo:

ProbandLabel: Wilson_Wisconsin kindred proband

Variant: NM_171998.4(RAB39B):c.503C>A (p.Thr168Lys)

ClinVar: 156532

CAID:

gnomAD: NR

FamilyAddInfo: Family is noted to be of German ancestry, and no consanguinity is noted.

FamilyPMIDs: 1674730, 4025396

Case#: Wilson_Australian kindred_Person II:2

Demographics: Male, 44y at diagnosis, Australia

CasePresentingHPOs: HP:0000750, HP:0001249, HP:0007351, HP:0002362, HP:0002067, HP:0100660, HP:0002396, HP:0000256

Age at onset <2y, while age at tremor onset was 38y. Birth and early milestones were normal. Early learning difficulties were reported and the proband was able to read and write. Parkinsonism classification was akinetic-rigid. Proband showed L-Dopa response, hypokinetic dysarthria, and normal cerebellar function. Other normal features included normal eye examination, MRI, Fragile X testing, karyotype, Copper testing, blood count and chemistry, urine metabolic testing and hearing.

CaseNotHPOs:

CasePreviousTesting: Linkage analysis using homozygous recessive model identified no linkage to autosomes, but to two regions: Xp22.2 and Xq27.3–qter

CaseMethod1: Copy number variation analysis

CaseMethod2: PCR

CaseGenotypingMethod: A ~45-kb deletion within the Xq haplotype was identified that encompassed the complete RAB39B gene and the last 3 coding exons of CLIC2.

Variant: NC_000023.11:g.(155246216_?)_(?_155288781)del

ClinVar: 157665

CAID:

gnomAD:

VariantEvidence: The proband was hemizygous for the ~45-kb deletion encompassing the complete RAB39B and partial CLIC2 genes. Expression of both transcripts was absent from fibroblast cells of affected individuals. The proband is not scored any points as the variant involves deletion of part of an additional gene, CLIC2. Although the authors ruled out seizures and cardiac anomalies (phenotypes associated with CLIC2 missense variant) in patients from the family, it is not conclusive that CLIC2 deletion does not have any impact on the proband's phenotype.

CaseAddInfo: The proband's siblings were also similarly affected. Elder brother of the proband died at 48y from positional asphyxia, and postmortem neuropathological studies on proband's brain showed pallor of the substantia nigra and locus coeruleus. H&E staining of substantia nigra revealed PD features, including loss of pigmented neurons and Lewy bodies in surviving neurons. Abundance of cortical Lewy bodies, were noted. Tau-immunoreactive NFTs were also observed in a small proportion of the surviving pigmented SN neurons

CasePMIDs:

Wilson_Wisconsin kindred

Family#PresentingHPOs: HP:0001263, HP:0000750, HP:0001249, HP:0002174, HP:0007351, HP:0002362, HP:0002067, HP:0002396, HP:0001260, HP:0000256, HP:0002007, HP:0000218, HP:0001355,

Age at clinical evaluation <2y; early learning difficulty with ability to read and live independently (in some members), age at tremor onset 10-20y, age at Parkinson diagnosis 20s, absent response to L-Dopa, hypokinetic dysarthria, skin depigmented papules, normal cerebellar function and eye examination, normal karyotype, normal copper testing, normal blood count and chemistry, normal urine metabolic testing, normal hearing.

FamilyNotHPOs:

Fragile X syndrome,

CountryOrigin: Germany

Ethnicity:

Race:

Family#PreviousTesting: Multipoint linkage analysis was performed. X chromosome exome sequencing revealed no other variants in the linkage region. Direct sequencing of CLIC2 ruled out variants in the gene.

Family#Method1: Sanger seq

Family#Method2:

Family#GenotypingMethod: RAB39B was directly sequenced

Affected: 16

Unaffected:

Segregations:

PublishedLOD: 6.75

eLOD:

AddSegregationInfo:

ProbandLabel: Wilson_Wisconsin kindred proband

Variant: NM_171998.4(RAB39B):c.503C>A (p.Thr168Lys)

ClinVar: 156532

CAID:

gnomAD: NR

FamilyAddInfo: Family is noted to be of German ancestry, and no consanguinity is noted.

FamilyPMIDs: 1674730, 4025396