MonDO: MONDO:0032706

Case: Chinese male. Onset at age 30 years with mild dysarthria with progressive worsening.

DiseaseAssertion: Cerebellar ataxia

FamilyInfo: No history of neurological disease and consanguinity was documented in the family. Delivery and perinatal events were unremarkable.

CasePresentingHPOs: HP:0001260, HP:0002141, HP:0002061, HP:0009046 (Dysarthria, Gait imbalance, Lower limb spasticity, Difficulty running

CaseHPOFreeText: Difficulty writing, Increase in bilateral knee reflexes

CaseNOTHPOs: HP:0003487 (Babinski sign)

CasePreviousTesting: His clinical examination displayed cerebellar ataxia with abnormal finger-to-nose and heel-knee-shin tests. Bilateral knee reflexes were symmetrical increased (+++) and Babinski signs were negative. Cranial nerves, muscle strength and sensory examinations were normal. Mild cognitive decline with a Mini-Mental State Examination (MMSE) of 24/30, a Scale for the Assessment and Rating of Ataxia (SARA) score of 17.5/40 and International Cooperative Ataxia Rating Scale (ICARS) score of 46/100. Brain MRI revealed cerebellar atrophy (Fig. 1A).

GenotypingMethod: WES with Sanger confirmation and co-segregation analysis. Genetic testing for spinocerebellar ataxias (SCAs) 1, 2, 3, 6, 7, 12, 17 and dentatorubral-pallidoluysian atrophy (DRPLA) were negative.

VariantEvidence: Wildtype and mutant plasmids were transfected into SH-SY5Y cells. The mRNA level of frameshift variant p.Thr442fs7 was almost same with the level of wild-type, whereas nonsense variant p.Arg253 was even increased, thus they might escape NMD. As a result, p.Gln316 and p.Ser436fs36 mutant GDAP2 proteins were barely detectable, p.Thr442fs7, p.His400fs15 and p.Arg253 generated truncated proteins. Western blot analysis indicated that the GDAP2-Arg253 and GDAP2-Thr442fs*7 were C-terminal deletion mutants.

MultipleGeneVariants:

(1) GeneName: GDAP2

(1) Variant: c.757C>T (p.Arg253*)

(1) ClinVarID or CAID: CA1031554

(1) gnomAD: Total AF 0.00001860, gnomAD v4.1 (https://gnomad.broadinstitute.org/variant/1-117899096-G-A?dataset=gnomad_r4)

(2) GeneName: GDAP2

(2) Variant: c.1323delC (p.Thr442fs*7)

(2) ClinVarID or CAID: CA2586967196

(2) gnomAD: not found in gnomAD v4.1

MonDO: MONDO:0032706

Case: Chinese male. Onset at age 30 years with mild dysarthria with progressive worsening.

DiseaseAssertion: Cerebellar ataxia

FamilyInfo: No history of neurological disease and consanguinity was documented in the family. Delivery and perinatal events were unremarkable.

CasePresentingHPOs: HP:0001260, HP:0002141, HP:0002061, HP:0009046 (Dysarthria, Gait imbalance, Lower limb spasticity, Difficulty running

CaseHPOFreeText: Difficulty writing, Increase in bilateral knee reflexes

CaseNOTHPOs: HP:0003487 (Babinski sign)

CasePreviousTesting: His clinical examination displayed cerebellar ataxia with abnormal finger-to-nose and heel-knee-shin tests. Bilateral knee reflexes were symmetrical increased (+++) and Babinski signs were negative. Cranial nerves, muscle strength and sensory examinations were normal. Mild cognitive decline with a Mini-Mental State Examination (MMSE) of 24/30, a Scale for the Assessment and Rating of Ataxia (SARA) score of 17.5/40 and International Cooperative Ataxia Rating Scale (ICARS) score of 46/100. Brain MRI revealed cerebellar atrophy (Fig. 1A).

GenotypingMethod: WES with Sanger confirmation and co-segregation analysis. Genetic testing for spinocerebellar ataxias (SCAs) 1, 2, 3, 6, 7, 12, 17 and dentatorubral-pallidoluysian atrophy (DRPLA) were negative.

VariantEvidence: Wildtype and mutant plasmids were transfected into SH-SY5Y cells. The mRNA level of frameshift variant p.Thr442fs7 was almost same with the level of wild-type, whereas nonsense variant p.Arg253 was even increased, thus they might escape NMD. As a result, p.Gln316 and p.Ser436fs36 mutant GDAP2 proteins were barely detectable, p.Thr442fs7, p.His400fs15 and p.Arg253 generated truncated proteins. Western blot analysis indicated that the GDAP2-Arg253 and GDAP2-Thr442fs*7 were C-terminal deletion mutants.

MultipleGeneVariants:

(1) GeneName: GDAP2

(1) Variant: c.757C>T (p.Arg253*)

(1) ClinVarID or CAID: CA1031554

(1) gnomAD: Total AF 0.00001860, gnomAD v4.1 (https://gnomad.broadinstitute.org/variant/1-117899096-G-A?dataset=gnomad_r4)

(2) GeneName: GDAP2

(2) Variant: c.1323delC (p.Thr442fs*7)

(2) ClinVarID or CAID: CA2586967196

(2) gnomAD: not found in gnomAD v4.1