Giannandrea_Family_MRX72

Family#PresentingHPOs: HP:0002342, HP:0010864, HP:0001250, HP:0000729

FamilyNotHPOs:

CountryOrigin: Italy

Ethnicity:

Race:

Family#PreviousTesting: X-linked intellectual disability was mapped to Xq28

Family#Method1: PCR

Family#Method2: Sanger

Family#GenotypingMethod: Both exons of the RAB39B gene were amplified by PCR and directly sequenced

Affected: 5

Unaffected:

Segregations: 7

PublishedLOD:

eLOD: 2.1

AddSegregationInfo:

ProbandLabel: Giannandrea_Family_MRX72_Proband III-4

Variant: NM_171998.4(RAB39B):c.215+1G>A

ClinVar: 10542

CAID:

gnomAD:

FamilyAddInfo:

FamilyPMIDs: 11050621

TissueExpression/Uberon ID: UBERON:0000955

ExpressionEvidence: qRT-PCR on several human and mouse tissues revealed that RAB39B was enriched in the brain. In theh developing mouse brain, Rab39b expression was constant between P1-P10 and P20-P180. Between P10-P20, Rab39b was upregulated 2-fold. Rab39a transcript levels were 10x lesss that Rab39b. The authors established that Rab39b was a neuron-specific gene, with highest expression in the hippocampus, and specifically in neuronal precursors and neurons only.

Where in paper: Figure 2

Giannandrea_Family X (D-23)

Family#PresentingHPOs: HP:0001256, HP:0002342, HP:0010864, HP:0000256, HP:0004322,

FamilyNotHPOs: HP:0001999

other malformations

CountryOrigin:

Ethnicity:

Race:

Family#PreviousTesting: X-linked intellectual disability was mapped to Xq28

Family#Method1: PCR

Family#Method2: Sanger sequencing

Family#GenotypingMethod: Both exons of the RAB39B gene were amplified by PCR and directly sequenced

Affected: 6

Unaffected:

Segregations: 5

PublishedLOD:

eLOD: 1.5

AddSegregationInfo: III-3 and III-4 are noted to be twins. To be conservative, only one segregation is counted, assuming monozygotic twins

ProbandLabel: Giannandrea_Family X (D-23)_Proband II-3

Variant: NM_171998.4(RAB39B):c.21C>A (p.Tyr7Ter)

ClinVar: 10543

CAID:

gnomAD: NR

FamilyAddInfo:

FamilyPMIDs:

NonPatientCell: EFO:0005214

GOterm: GO:0016192

GeneAlteration: Undifferentiated N2A cells (murine neuroblastoma cell line) were infected with shRNAs to downregulate endogenous Rab39b expression by 45%.

FunctionalEvidence: N2A cells 4d after treatment with shRNA showed a change in morphology. Clumps of actin and reduced and/or altered membrane protrusions were observed. Rescue with WT RAB39B was able to restore the normal actin and cytoskeletal morphology, indicating that Rab39b may alter intracellular vesicular trafficking steps essential for membrane remodeling.

FAVariants:

NonPatientCell: CL:0002608

GOterm: GO:0016192

GeneAlteration: Rab39b expression was knocked down in mouse primary hippocampal neurons using shRNA

FunctionalEvidence: Expression of Rab39b was reduced by 40% as determined by RT-PCR. Morphological analysis showed significant alteration and the number of growth cones was decreased at each neurite terminal. Authors also show that RAB39B was localized to growth cones and could be involved in intracellular trafficking related to membrane recycling of Golgi-derived vesicles. Therefore RAB39B gene alterations can lead to impaired trafficking and lead to accumulation in membrane content and disorganized growth of growth cones.

FAVariants:

PMID: 28851564

Gene: RAB39B

Disease: early-onset parkinsonism-intellectual disability syndrome

MonDO: MONDO:0010709

Notes: The family reported has a phenotype of ID and autism. Parkinson disease or clinical features of Parkinsonism are not noted in any patients. Proband may be scored upon expert review.

Mata_Family

Family#PresentingHPOs: Members of the family were diagnosed with Parkinson's disease and met UK PD Society Brain Bank clinical diagnostic criteria for PD

FamilyNotHPOs:

CountryOrigin: US (European origin)

Ethnicity:

Race:

Family#PreviousTesting:

Family#Method1: WES

Family#Method2: Sanger

Family#GenotypingMethod: Whole exome sequencing was performed in 4 affected and 1 unaffected individuals and confirmed by Sanger. The rest of the affected individuals were also genotyped

Affected: 6

Unaffected:

Segregations: 7

PublishedLOD:

eLOD: 2.1

AddSegregationInfo:

ProbandLabel: Mata_Family_Proband III-10

Variant: NM_171998.4(RAB39B):c.574G>A (p.Gly192Arg)

ClinVar: 218362

CAID:

gnomAD: NR

FamilyAddInfo:

FamilyPMIDs:

PMID: 26399558

Gene: RAB39B

Disease: early-onset parkinsonism-intellectual disability syndrome

MonDO: MONDO:0010709

InheritancePattern: X-linked

Case#: Lesage_Proband

Demographics: Male, 39y at report, France

CasePresentingHPOs: HP:0001300, HP:0002322, HP:0001256, HP:0100660, HP:0002451, HP:0100710,

Proband was diagnosed with early-onset Parkinsonism. Proband had asymmetric rest tremor, akineto-rigid syndrome, and showed good response to Levodopa and normal brain MRI. He required sheltered employment due to intellectual disability. 8y after disease onset, patient developed treatment-related complications including motor fluctuations. Proband showed good global cognitive performance but difficulty concentrating and subcortico-frontal signs. Psychiatric interview revealed dysthymic disorder. Proband died at 55y, after apomorphine treatment was initiated.

CaseNotHPOs: No pyramidal, cerebellar, or ocular disorders

CasePreviousTesting: Exome analysis in the patient excluded variants in all other known PD genes.

CaseMethod1: WES

CaseMethod2:

CaseGenotypingMethod: The variant was identified by data mining exomes for coding and splice site variants in RAB39B.

Variant: NM_171998.4:c.557G>A (p.Trp186Ter)

ClinVar:

CAID: CA414923761

gnomAD:

VariantEvidence: The proband was hemizygous for the null variant, Trp186Ter in exon 2/2. NMD is not predicted. The evidence is scored reduced points. (0.5)

CaseAddInfo: No family history of PD is reported.

CasePMIDs:

PMID: 28851564

Gene: RAB39B

Disease: early-onset parkinsonism-intellectual disability syndrome

MonDO: MONDO:0010709

Notes: The proband reported has clinical features of neurofibromatosis, with a de novo donor splice site variant in NF1, as well as a 12-bp deletion in RAB39B, which the authors assert was responsible for the phenotypes of severe ID, behavioral problems and aggressiveness.

Case#: Ciammola_Family 1_Proband IV-2

Demographics: Male, 49y at report

CasePresentingHPOs: HP:0002378, HP:0002067, HP:0002172, HP:0002322, HP:0000729, HP:0100543, HP:0000338, HP:0002063, HP:0002067, HP:0002174,

Onset of bradykinesia and postural instability at 44yo. Rest tremor developed in the right hand and then spread bilaterally. Gait was slow. Fronto-subcortical involvement pattern was seen on neurological assessment.

CaseNotHPOs:

CasePreviousTesting:

CaseMethod1:

CaseMethod2:

CaseGenotypingMethod:

Variant: NM_171998.4:c.370del (Lys124SerfsTer10)

ClinVar:

CAID: CA658795322

gnomAD: NR

VariantEvidence: The proband was hemizygous for the frameshift variant, Lys124SerfsTer10, but showed mosaicism. Segregation analysis in the family revealed that the variant was de novo and proband cDNA analysis showed normal and mutant transcripts in a 1:1 ratio, and this was also confirmed in oral mucosa cells and urine. Immunoblotting of HeLa cells transfected with variant RAB39B revealed complete loss of function.

CaseAddInfo:

CasePMIDs:

Case#: Ciammola_Family 1_Proband II-3

Demographics: Male, 67y

CasePresentingHPOs: HP:0002378, HP:0002174, HP:0030186, HP:0002135, HP:0002322, HP:0001288, HP:0002067, HP:0001276,

Developmental milestones were unremarkable, but experienced severe learning disabilities at primary school. Proband developed a postural tremor in both hands at 11yo. At 44y, he was diagnosed with essential tremor in both hands and CT scan revealed left basal ganglia calcification. He developed progressive rest tremor in right hand and progressive gait difficulty from 62yo. Bradykinesia at finger tapping, slow gait, decreased arm swing, especially on the right side, and good response to L-dopa therapy were noted. Mild-moderate front-subcortical involvement pattern

CaseNotHPOs:

CasePreviousTesting: No pathogenic variants were detected in GBA, LRRK2 exons 29-30-31-35-41, PRKN, PINK1, DJ-1, ATP13A2, FBXO7, PLA2G6, DNAJC6 and SYNJ1 analyzed by Sanger sequencing. No deletion/duplications in PRKN analyzed by quantitative PCR were detected.

CaseMethod1: Sanger

CaseMethod2:

CaseGenotypingMethod: RAB39B gene was sequenced.

Variant: NM_171998.4:c.137dup

ClinVar:

CAID: CA658795323

gnomAD: NR

VariantEvidence: The proband was hemizygous for the frameshift variant, Ser47LeufsTer44. Immunoblotting in HeLa cells transfected variant RAB39B revealed absence of RAB39B protein, indicating complete loss of function due to the variant.

CaseAddInfo:

CasePMIDs:

PMID: 28851564

Gene: RAB39B

Disease: early-onset parkinsonism-intellectual disability syndrome

MonDO: MONDO:0010709

PMID: 33364235

Gene: RAB39B

Disease: early-onset parkinsonism-intellectual disability syndrome

MonDO: MONDO:0010709

NonHumanModel: Niu_Mouse

GeneAlteration: Transcription activator like effector nuclease (TALEN) - mediated strategy was used to target exon 1 of RAB39B to generate the knockout mice in the C57BL/6J background. A mouse line with a "GT" deletion at nucleotide 106-107 that caused a frameshift and early truncation of RAB39B was obtained. Authors confirmed absence of RAB39B loss of fucntion.

ModelPhenotype: Learning and memory deficits

HumanPhenotype: HP:0001249

ModelEvidence: 2-mo hemizygous male knock-out (KO) mice showed behavioral alterations compared to WT mice. KO mice showed reduced anxiety, impaired recognition memory, impaired short-term working memory, impaired spatial memory, impaired social novelty recognition, compromised motor skill learning, but motor ability was not affected. Authors indicate that impaired learning and memory was associated with altered synaptic plasticity.

ModelVariant:

WhereInPaper:

The evidence is scored minimal points as the phenotype recapitulated aligns with the human ID phenotype; however, the model provides no evidence of Parkinson disease phenotype. (0.5)

NonHumanModel: Zhang_Mouse

GeneAlteration: Exon 2 of RAB39B was targeted using two gRNAs and Cas9 mRNA in the C57BL/6N background. Mice harboring 397-bp deletions in exon 2 were obtained.

ModelPhenotype: HP:0000256 Social and memory deficits

HumanPhenotype: HP:0001249, HP:0000256

ModelEvidence: Similar to PMID: 33364235, authors show through ASD-related tests that KO mice exhibit social and memory deficits. They also show that RAB39B variation results in over-proliferation and differentiation deficits of neural progenitor cells, which results in larger that normal number of neurons. Mice therefore have macrocephaly.

ModelVariant:

WhereInPaper:

The model is scored reduced points as the mice recapitulate the ASD phenotype seen in some human patients with RAB39B variants, but does not provide evidence for the Parkinson disease phenotype. (0.5)

PMID: 32670181

Gene: RAB39B

Disease: early-onset parkinsonism-intellectual disability syndrome

MonDO: MONDO:0010709

Notes: The report analyzed RAB39B variation in a cohort of 176 individuals with early-onset Parkinson disease by copy number variation analysis, 5' and 3' UTR analyses. However, variants identified were classified as likely benign or uncertain significance.

PMID: 24357492

Gene: RAB39B

Disease: early-onset parkinsonism-intellectual disability syndrome

MonDO: MONDO:0010709

InheritancePattern: X-linked

Notes: Functional evidence?

Case#: Shi_Proband III-1

Demographics: Male, 20y, China

CasePresentingHPOs: HP:0001300, HP:0001256, HP:0001337, HP:0002071, HP:0002063, HP:0007076, HP:0200085, HP:0001288,

Pregnancy, delivery nd perinatal period were normal. Learning difficulties were identified at 8y. Age at tremor onset was 12y. Hoehn and Yahr staging was 2.5. T1, T2, and Susceptibility Weighted Imaging (SWI)-weighted brain MRI showed low-signal intensities in the bilateral globus pallidus, whereas CT scan showed high-density calcification in the same area. Treatment with Levodopa resulted in slight relief from tremor. Unified Parkinson’s Disease Rating Scale (UPDRS) - 32; Montreal Cognitive Assessment (MoCA) - 15; Mini-Mental State Examination (MMSE) - 20

CaseNotHPOs:

CasePreviousTesting:

CaseMethod1: WES

CaseMethod2: Sanger

CaseGenotypingMethod: WES was performed, followed by sequencing of the entire RAB39B coding region and exon-intron boundaries.

Variant: NM_171998.4:c.536dup (Ile180Aspfs*48)

ClinVar: CA1139768479

CAID:

gnomAD: NR

VariantEvidence: The proband was hemizygous for the null variant, Ile180AspfsTer48. The variant is predicted to cause extension of the protein with loss of the natural stop codon. In the absence of functional evidence supporting loss of function due to the variant, reduced points are awarded.

CaseAddInfo: Proband's parents were noted to be nonconsanguineous

CasePMIDs:

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