Case#: female; age 65

DiseaseAssertion: chemotherapy-induced cardiomyopathy with severe left ventricular systolic dysfunction

FamilyInfo: NR

ParentalTesting: NR

CasePresentingHPOs: HP:0001644 HP:0001635 HP:0001640

CaseHPOFreeText: Dilated left ventricle; left ventricular dysfunction; cardiomegaly; bilateral pleural effusion; dyspnea

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

CasePreviousTesting: Previous anthracycline-associated cardiomyopathy 7 years earlier

Genotyping Method: TruSight One Expanded 6700-gene sequencing panel on an Illumina NextSeq 550

FunctionalAnalysis: NR

Variant: c.452G>A (p.Arg151Gln; rs730881101); missense variant; heterozygous

ClinVar: 181617

CAID: NR

gnomAD: NR

Variant: carrier status, considering that she was clinically asymptomatic and that she also had normal values for alpha-glucosidase activity on DBS analysis but she was heterozygous only for the c.2560C>T (rs121907943, p.Arg854Ter) pathogenic mutation

Variant: found reduced alpha-glucosidase activity on DBS assessment and the same pattern of mutations seen on the sister described above (II-6): (c.-32-13T>G (rs386834236, intronic) and c.2560C>T (rs121907943, p.Arg854Ter))

Case II-6: 56, Female

CasePresentingHPOs: hypertension, proximal weakness, with occasional cramping in both of her lower limbs, voice sounded particularly nasal, mild scapular winging, slight muscular atrophy on temporal, deltoids and thigh muscle extensors, mild lordosis

CasePresentingHPOsFreeText: Pain, temperature, vibration and proprioception were preserved as well as her coordination. myopathic pattern with reduced duration and amplitude of motor unit action potentials (MUAPs) specifically on thigh extensors

CaseNOTHPOS: dysphagia or dysphonia

CaseNOTHPOSFreeText: did not find paraspinal complex repetitive discharges, did not find any alteration on the tissue specimen analysis using hematoxylin and eosin

Variant: reduction in alpha-glucosidase activity (Neutral/acid: 61.0, reference: <30) and her GAA gene sequencing showed the two same pathologic heterozygous compound mutations found on our first subject (II-8) (c.-32-13T>G (rs386834236, intronic) and c.2560C>T (rs121907943, p.Arg854Ter))

*she did not have the third variant found on subject II-8 (c.1551+42G>A (rs115427918, intronic))

Case II-8: 50, male

CasePresentingHPOs: HP:0002094 (Dyspnea), HP:0002015 (Dysphagia), HP:0000822 (Hypertension), HP:0005978 (Type II diabetes mellitus), HP:0003119 (Abnormality of lipid metabolism), HP:0001271 Polyneuropathy, HP:0009055 (Generalized muscle wasting, Generalized muscle atrophy), HP:0001265 (Hyporeflexia), HP:0003487 (Babinski sign), HP:0031993 (Hoffmann sign),

CasePresentingHPOsFreeText:: fully conscious, alert and able to follow order, receiving intravenous gamma-globulin therapy because a chronic inflammatory demyelinating polyneuropathy (CIDP), cranial nerves were normal while motor examination showed a symmetrical 2/5 proximal and 4/5 distal strength, referred allodynia in the soles and distal part of both legs, and was not able to stand or walk, pulmonary evaluation revealed bilateral reduced breath sounds, denervation and spontaneous activity with complex repetitive discharges on muscles associated with cranial nerves and within cervical, thoracic and lumbar areas, predominantly demyelinating, mixed sensorimotor polyneuropathy, with absence of F waves, tested for Pompe disease on dried blood spot (DBS) analysis that confirmed an alpha-glucosidase reduced activity

CaseNOTHPOSFreeText: Cardiologic examination was unremarkable

Variant: two pathogenic compound heterozygous mutations: c.-32-13T > G (rs386834236, intronic), c.2560C>T (rs121907943, p.Arg854Ter); and one variant of unknown significance: c.1551+42G>A (rs115427918, intronic).

Variant: only two daughters (III-9 and III-10) of our subject II-6 had marginally altered DBS reports (Neutral/acid: 36.0 and 38.1, reference: <30) and both of them also carried one of the mutations (c.2560C>T (rs121907943, p.Arg854Ter)) already identified on their mother. *Despite both of them having borderline results on one single DBS assessment, we have still considered them to have a carrier status in view of that they have remained asymptomatic until now.

Case# F1_IV:5, M, 6.5yo report, Saudi Arabia

CasePresentingHPOs HP:0001263, HP:0008947, HP:0001257, HP:0000486, HP:0000639, HP:0004326, HP:0000252

HPOcont: Global developmental delay, Infantile muscular hypotonia, Spasticity, Strabismus, Nystagmus, Cachexia, Microcephaly

Free text: "At 4.5 years of age, he was cachectic with a weight of 8.1 kg (−5.2 SD), short with a length of 89 cm (−3.7 SD), and microcephalic with a head circumference of 46 cm (−3.2 SD). He was inattentive and had no visual tracking ability as well as bilateral strabismus and nystagmus. He had severe axial hypotonia and appendicular hypertonia with spasticity."

CaseNotHPOs HP:0001250

NotHPOcont: Seizures

CasePreviousTesting "Plasma lactate, ammonia, uric acid, lipid profile, tandem mass spectrometry (MS), urine organic acids, plasma amino acids, and congenital disorder of glycosylation screenings did not reveal any abnormality. Chromosomal analysis and microarray were unremarkable. Glycosaminoglycans and oligosaccharides in the urine were normal. Lysosomal enzyme analysis was unremarkable. HEXB and SMN1 mutation analysis did not reveal pathogenic mutations. Brain MRI showed mild diffuse brain atrophy, and MRS (magnetic resonance spectroscopy) showed a mild reduction of the N-acetylaspartate peak but a normal lactate peak. Skeletal survey showed diffuse osteopenia."

CaseMethod1 Exome sequencing

CaseMethod2 Sanger

CaseGenotypingMethod autozygome filtering after exome sequencing, confirmed with sanger

Variant NM_032504.1(UNC80):c.3793C>T (p.Arg1265Ter)

ClinVar 219188

gnomAD 0.00004175(Latino), 0.000006613(Overall)

CaseAddInfo His first-cousin parents had two sons who died at 4 and 6 years of age with a reportedly identical phenotype of profound static encephalopathy and no seizures. The index individual has two living brothers and two sisters who are all healthy

Family#PresentingHPOs HP:0001290, HP:0001508, HP:0001263

HPOcont: Hypotonia, Failure to thrive, Global developmental delay

FamilyNotHPOs HP:0000486, HP:0000639, HP:0004326, HP:0000252, HP:0002353

NotHPOcont: Strabismus, Nystagmus, Cachexia, Microcephaly, EEG abnormality

CountryOrigin Saudi Arabia

Family#PreviousTesting Brain MRI showed normal parenchyma asnd myelination in F2 individuals, mild diffuse brain atrophy in F1_IV:5

Family#Method1 Sanger

Family#GenotypingMethod Exome sequencing on "one of the three affected members" then confirmed in remaining members with Sanger

Affected 3

Unaffected 7

PublishedLOD 4.7 (Combined with Family 1)

AddSegregationInfo consanguinity

ProbandLabel F1_IV:5

CasePresentingHPOs HP:0001263, HP:0001508, HP:0001290

HPOcont: Global developmental delay, Failure to thrive, Hypotonia

CaseNotHPOs HP:0001250

NotHPOcount: Seizures

Variant NM_032504.1(UNC80):c.3793C>T (p.Arg1265Ter)

ClinVar 219188

gnomAD 0.00004175(Latino), 0.000006613(Overall)

Family 1: individuals II-2 and II-5 underwent homozygosity mapping which resulted in the finding of homozygous regions on chromosome 18 between rs1944983 and rs2194631 in both individuals - This region carries some SERPIN genes

Supplementary Table 1 (7 cols x 6 rows)

Nucleotide position Type of variation rs ID 1000 Genome MAF % ESP MAF %<br /> Italian Controls (MAF%) SALS (MAF %) c.909A>G p.Val303Val rs141922502 0.18 0.477 37/3960 (0.47) 14/1106 (0.6) c.999C>T p.Ala333Ala rs147351423 0.32 0.19 20/3960 (0.25) 2/1106 (0.1) c.1257C>T p.Ser419Ser rs199590938 0.01 § - - 1/1106 (0.05) c.376-16C>T Intronic rs116486324 0.16 0.21 n.c. 1/1106 (0.05) c.8G>A 3’UTR rs142720001 0.02 0.023 4/3960 (0.05) 1/1106 (0.05) c.48G>A 3’UTR rs11556349 1.7 0.845 46/3960 (0.58) 4/1106 (0.18)

Korean stroke patients who were carriers of COQ5 rs10849757 were more associated with statin related myotoxicity risk than wild-type homozygote carriers (GG) (9.7% vs. 3.9%, p = 0.024). Only group demographics provided rather than individual phenotype/genotype information

Case#: 34 y.o female proband, caucasian(German), diagnosed with Stargardt, late onset.

DiseaseAssertion: STGD

FamilyInfo: Unaffected father, mother exhibiting retinal disease. Biparental history of glaucoma and AMD, pattern dystrophy on maternal side.

CasePresentingHPOs:HP:0001129, HP:0007722 ,HP:0007663, HP:0030329, HP:0007814, HP:0000608

CaseHPOFreeText: Proband exhibits retinal thinning in all retinal layers, alongside chorioretinal atrophy. Experienced increased central vision loss over the course of a decade. At time of study, diagnosed with Stargardt disease. Visual acuity 20/200 in right eye and 20/40 in left. Additionally found granular molting of retinal pigment epithilium.

CaseNotHPOs:n/a

CaseNotHPOFreeText:n/a

Genotyping Method: WES and variant calling performed at Columbia Institute for Genomic Medicine.

PreviouslyPublished:n/a

Variant: rs61751407, c.5714+5G>A

ClinVar: 432057

CAID: n/a

SupplementalData: n/a

This variant is well-known in exon 42, [M2]: c.5882G > A; p.(Gly1961Glu), rs1800553. The father of the affected patient was deceased; however, the mother was found to be homozygous for the wild type (WT) allele. According to the ACMG standards, M2 is likely pathogenic.