Case# Fam1Pat1, F, 21yo onset, Turkish

CasePresentingHPOs HP:0002061, HP:0002066, HP:0002070, HP:0001260, HP:0001310, HP:0000563, HP:0006986,

CasePreviousTesting Neurologic examination revealed dysarthria, spasticity in lower >> upper extremities, mild weakness in proximal leg muscles, Achilles tendon contracture, mild dysmetria, dysdiadochokinesia, and a spastic-ataxic gait. Cranial MRI and nerve conduction studies were unremarkable.

CaseMethod1 Whole Exome

Variant NM_001198868.1:c.994G>A

CAID CA381247865

gnomAD 0.00005842(East Asian), 0.000008204(Overall)

VariantEvidence none

Case# Fam2Pat1, F, Turkish, 15yo onset

CasePresentingHPOs HP:0002061, HP:0002066, HP:0002070, HP:0001260, HP:0001310, HP:0000563, HP:0006986

CasePreviousTesting Neurologic examination revealed severe spasticity in the lower and mild spasticity in the upper extremities, hyperactive deep tendon reflexes, bilateral extensor plantar responses, and patellar clonus. The Hoffmann sign was positive. She had bilateral mild dysmetria and dysdiadochokinesia. Nerve conduction studies, EMG, sensory evoked potential tests, and MRI did not reveal any pathology

CaseMethod1 Whole Exome

Variant NM_001198869.1:c.1176G>A

CAID CA6093326

VariantEvidence premature stop codon

gnomAD 1.554e-05(European (Non-Finnish)), 8.513e-06(Overall)-Exac

Variant NM_001198868.1(CAPN1):c.1579C>T (p.Gln527Ter)

ClinVar 225766

Variant NM_005186.3(CAPN1):c.407delC (p.Pro136Argfs), NM_001198868.1(CAPN1):c.1605+5G>A

ClinVar 225767, 225768

gnomAD none, 0.0003171

Case# FamilyC:IV-13, 33 AoO, Female, USA

CasePresentingHPOs HP:0002064, HP:0001258, HP:0002355

CaseMethod1 WES

CaseMethod2 Sanger

Variant NM_005186.3(CAPN1):c.407delC (p.Pro136Argfs), NM_001198868.1(CAPN1):c.1605+5G>A

ClinVar 225767, 225768

gnomAD none, 0.0003171

CaseAddInfo nonconsanguineous family

Family#PresentingHPOs HP:0001258, HP:0002460, HP:0007067, HP:0002395

CountryOrigin Morocco

Race White

Family#Method1 WES

Family#Method2 Sanger

Affected 4

Unaffected 3

Segregations 4

eLOD 1.93

AddSegregationInfo consanguineous

ProbandLabel FamilyB:IV-1 age of onset 35, Male

Variant NM_001198868.1(CAPN1):c.1579C>T (p.Gln527Ter)

ClinVar 225766

FamilyAddInfo Fig 1

Case# SAL-399-073, Female, 46yo, French, Hispanic

CasePresentingHPOs HP:0002385, HP:0011448, HP:0001260, HP:0002066, HP:0002015, HP:0002650, HP:0001272

CaseMethod1 Exome

CaseMethod2 Sanger

Variant NM_005186.3:c.463C>T(p.Q155X), NM_005186.3:c.1142C>T(p.R512C)

CAID CA381242841, CA381248914

gnomAD 0.00003567

VariantEvidence nonsense, missense in trans with null variant

CaseAddInfo in article supplement

Case# Tun66275, Female, 20, Tunisia

CasePresentingHPOs HP:0002066, HP:0001260, HP:0001257

CaseNotHPOs HP:0001272

CaseMethod1 Exome

CaseMethod2 Sanger

Variant NM_005186.3:c.1534C>T(p.R512C)

CAID CA6093457

gnomAD 0.000008977

VariantEvidence none

CaseAddInfo in supplement

Case# SAL-584-005, Female, 67yo, Italian

CasePresentingHPOs HP:0001258, HP:0002070, HP:0001260, HP:0002066

CaseMethod1 Exome

CaseMethod2 Sanger

Variant NM_005186.3:c.188dup

CAID CA6092966

gnomAD 0.000009815

VariantEvidence null

CaseAddInfo in supplement, possibly consanguineous family

Case# Family R III:1, Female, 43yo, Bangladesh

CasePresentingHPOs HP:0002066, HP:0001257, HP:0002015, HP:0001260, HP:0001272

CaseMethod1 DNA SNP array

CaseMethod2 Exome sequencing

Variant NM_005186.3:c.337+1G>A

CAID CA381241741

VariantEvidence predicted null

Case# II-4, Female, 14, Ireland

CasePresentingHPOs HP:0002506, HP:0002497, HP:0002061, HP:0011448, HP:0001347

CasePreviousTesting Initial genetic testing (with patient consent) included a screening panel for HSP, as well as SCA 1, 2, 3 and 6, all of which were negative.

CaseMethod1 WES

Variant NM_005186.3:c.1534C>T(p.Arg512Cys)

CAID CA6093457

gnomAD 0.000008977

Case# Travaglini 1, Male, 16 report, Italian

CasePresentingHPOs HP:0006895, HP:0040083, HP:0001347, HP:0003487

CasePreviousTesting Sanger of SPG4 and 89 other known/candid genes by Nextera Custom Enrichment panel

CaseMethod1 Sanger Sequencing

CaseGenotypingMethod CAPN1 variants found in same panel screen

Variant NM_005186.3:c.221G>A (p.G74D), NM_005186.3:c.911C>T(p.T304M), NM_005186.3:c.1418G>T (p.R473L)

CAID CA6092976, CA6093221, CA6093432

gnomAD 0.0006904 , 0.0003415, 0.00003952

CaseAddInfo nonconsanguineous family

Case# Tadic Index, F, Turkish, 39yo report

CasePresentingHPOs HP:0001260, HP:0000514, HP:0001285, HP:0001276, HP:0001776, HP:0002070, HP:0002317

CasePreviousTesting The patient scored 4/40 on the Scale for the Assessment and Rating of Ataxia (SARA). Baclofen, tizanidine and tolperisone were not tolerated or inefficacious but she responded to botulinum toxin injections with a mean improvement of 40–50%. Her cranial MRI showed very mild cerebellar vermal atrophy, whereas spinal cord imaging was unremarkable

CaseMethod1 Whole Exome

Variant NM_001198869.1:c.759+1G>A

CAID CA381244789

gnomAD 0.00006707(African), 0.000004189(Overall)

VariantEvidence splice-site variant

CaseAddInfo in trans