PIK3CD (p.Glu525Gly)

PMID: 34692603 Case: Italian, Female child, 7-8yo DiseaseAssertion: NLH FamilyInfo: non-consanguineous parents, Italian, family and personal history were unremarkable, without any opportunistic or severe infection. CasePresentingHPOs: HP:0032203; HP:0011956, hematochezia, which progressively evolved into chronic bloody mucous diarrhea lasting for over 4 weeks, activated PI3 kinase δ syndrome (APDS) CaseHPOFreeText: Sugar intestinal permeability was markedly altered (lactulose/mannitol ratio 0.09, normal value < 0.03). Upper and lower gastrointestinal digestive endoscopy showed numerous small nodules throughout the entire gastrointestinal tract from the stomach to the rectum (Figures 1A–F), whose histopathologic features were consistent with the diagnosis of NLH (Figures 1G–I). No signs of chronic intestinal inflammation or autoimmune enteropathy, such as enterocyte apoptosis, were observed in the multiple biopsies taken at endoscopy. CaseNotHPOs: HP:0005202, HP:0034890, HP:0032247, HP:0033624, HP:0033431, HP:0033185, HP:0031693, HP:0020072, HP:0033508, HP:0033509, HP:0005215, HP:0002720, HP:0004433, HP:0011837 CaseNotHPOFreeText: HIV, bacterial Yersinia enterocolitica, cow's milk protein allergy, familial Mediterranean fever (FMF) (ORPHA:342), and other inborn errors of immunity (IEI) CasePreviousTesting: Stool culture, Fecal Calprotein, CRP, Erythrocyte sedimentation, ANCA, ASCA, GI endoscopy GenotypingMethod: Whole exome sequencing, Cell Culture, Western Blot. PreviouslyPublished: NR Variant: 582515, p.Glu525Gly (c.1574A>G) ClinVarID: 557431 CAID: CA338303813 gnomAD: n/a SupplementalData: The patient received a short course of steroids (oral prednisone at an initial dose of 1.5 mg/kg/day) with complete resolution of symptoms and normalization of calprotectin during treatment but rapid clinical and biochemical (i.e., calprotectin elevation) relapse upon discontinuation.

PatientID: 10

KindredID: 10

Case: M, 22Y0M, Caucasian

DiseaseAssertion: VHL

FamilyInfo: Positive family history.

CohortInfo: Case series of 14 patients with definite or presumed von Hippel-Lindau disease and retinal vascular proliferation.

CasePresentingHPOs: HP:0002011, HP:0001732, HP:0007850, HP:0012210, HP:0009711 (Morphological central nervous system abnormality, abnormality of the pancreas, retinal vascular proliferation, abnormal renal morphology, retinal capillary hemangioma)

CaseHPOFreeText: At age 12, his left eye had a large juxtapapillary vascular complex extending from the nerve along the superior arcade that was associated with dense fibrovascular tissue. During the next 29 months, this fibrovascular complex enlarged, extending into the center of the macula and causing a decrease in visual acuity to 20/80. The patient underwent pars plana vitrectomy and membrane peel. When the patient was reexamined 7 years after his surgery, there was no recurrence of the lesion. In the patient's contralateral right eye, 3 typical peripheral RCHs were observed during this 7-year follow-up. At age 14 years, he was also noted to have a small patch of superficial retinal vessels in the inferior retinal quadrant near the equator of the right eye that resembled an arteriovenous anastomosis.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Partial Deletion

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: deletion

CivicName:Null (Partial deletion)

MultipleGeneVariants: N/A

GroupID/ KindredID: 28

PatientID: II

Case: 24Y0M, Sex unknown, Polish

DiseaseAssertion: VHL

FamilyInfo: Family 28 consisted of 4 members; one relative (age 27Y) was found with multiple cerebellar HABs at 25Y, and multiple spinal HABs, another (40Y) diagnosed at 30Y with multiple cerebellar HABs, and multiple spinal HABs, and a final relative (62Y), diagnosed with a single HAB.

CasePresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

CaseHPOFreeText: Patient was diagnosed with a single cerebellar HAB at 24Y

GroupNotHPOs: HP:0009713; HP:0009711; HP:0005584 (spinal hemangioblastoma, retinal capillary hemangioma; renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: complete deletion of VHL gene

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: Haplotype analysis information in Table 3

MutationType: deletion

CivicName: deletion

MultipleGeneVariants: N/A

GroupID/ KindredID: 22

Case: Age unknown, Sex unknown, Chinese

DiseaseAssertion: hemangioblastoma

FamilyInfo: No family history. Genetic testing of their parents confirmed a de novo mutation.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0002666; HP:0005584; HP:0009711; HP:0001732 (pheochromocytoma; renal cell carcinoma; retinal capillary hemangioma; pancreatic lesion)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Exon 1 deletion

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVar: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence:N/A

MutationType: exon_loss_variant

CivicName: Exon 1 Deletion

MultipleGeneVariants: N/A

PatientID: unknown (brother)

KindredID: A

Case: M (deceased), Age unknown, Turkish

DiseaseAssertion: assumed VHL

FamilyInfo: 5 family members are grouped with this deletion (ages 16-37Y; mean 31Y). VHL was clinically diagnosed in, at minimum, the proband. See Fig. 2 for family pedigree. This patient and his one brother were not tested for the DNA deletion however it is assumed by the authors due to the segregation observed.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0009711; HP:0002666; HP:0005584 (retinal capillary hemangioma; pheochromocytoma; renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Deletion of exons 1 and 2

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: not tested for the DNA deletion however it is assumed by the authors due to the segregation observed.

MutationType: exon_loss_variant

CivicName: exon 1-2 deletion

MultipleGeneVariants: N/A

GroupID/ KindredID: F28

Case: Sex unknown, 23Y0M, Spanish

DiseaseAssertion: assumed VHL

FamilyInfo: familial antecedents found; unknown of any additional features of index case relatives

CasePresentingHPOs: HP:0000107; HP:0009711; HP:0006880; HP:0006770; HP:0002666 (renal cysts, retinal capillary hemangioma, cerebellar hemangioblastoma, clear cell renal cell carcinoma, pheochromocytoma)

CaseHPOFreeText: unilateral pheo, bilateral ccRCC and multiple lesions were found with the patient’s renal cysts. Age of onset is 23Y0M.

CaseNotHPOs: HP:0001737 (pancreatic cysts)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: rearrangement (unspecified)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: Southern blot positive

MutationType: rearrangement_region

CivicName: Rearrangement

MultipleGeneVariants: N/A

PatientID: 246

KindredID: 246

Case: Sex Unknown, 26Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797; HP:0009711; HP:0006770 (Hemangioblastoma, Retinal capillary hemangioma, Clear cell renal cell carcinoma)

CaseHPOFreeText: CNS and retinal hemangioblastoma and clear cell renal cell carcinoma.

CaseNotHPOs: HP:0002666; HP:0000107; HP:0001732 (Pheochromocytoma, Renal cyst, Abnormality of the pancreas)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished:N/A

SupplementalData: Table S1, S2 and S3

Variant: Partial Deletion (0.7kb)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: deletion

CivicName: Partial deletion of 0.7kb

MultipleGeneVariants: N/A

PatientID: IX-I

KindredID: 9

Case: M, 68Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: No family history reported.

CasePresentingHPOs: HP:0006748; HP:0002668; HP:0030405; HP:0001737; HP:0006880 (adrenal pheochromocytoma, paraganglioma, pancreatic endocrine tumor, pancreatic cyst, cerebellar hemangioblastoma)

CaseHPOFreeText: Patient presented with adrenal pheochromocytoma, paraganglioma, pancreatic endocrine tumor, pancreatic cyst, and cerebellar hemangioblastoma at age 55Y0M and was diagnosed with VHL type 2A (see table 2).

CaseNotHPOs: HP:0000107; HP:0005584 (renal cyst; renal cell carcinoma)

CaseNotHPOFreeText: Patient negative for renal cell carcinoma and renal cysts.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: complete deletion

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: deletion

CivicName: NULL (deletion)

MultipleGeneVariants: N/A

GeneName: DICER1 PMID: 28323992 PMCID: PMC5443331 *No HGNCID found Inheritance pattern: autosomal-dominant Disease Entity: multinodular goiter and thyroid cancer Mutation: Germline Zygosity: not listed Variant: c.3726C>A; p.Tyr1242a, c.3675C>G; p.Tyr1225a Family Information: 145 individuals with DICER1 germline mutations from 48 family controls (135 individuals) that lacked the DICER1 mutation Case: male and female carriers as well as family members were studied. Ages: 20, 30, and 40 for both populations (DICER1 carriers were significantly younger than controls}. Population from Great Britain, UK, and USA (no significant difference between race, ethnicity, or sex found). CasePresentingHPOs: no previous therapeutic radiation or chemotherapy. Thyroid cancer or MNG diagnoses were likely reported with the DICER1 mutation CasePreviousTesting: Sequencing performed with Sanger or next-generation sequencing assays. DICER1 carriers underwent testing to obtain thyroid-stimulating hormone, thyroxine, thyroxine-binding globulin, and serum albumin levels as well as medical history and physical examinations (+thyroid palpation). Participants were also given thyroid US examinations. gnomAD: n/a Mutation Type: missense

PatientID: None

KindredID: 1

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Adrenal pheochromocytoma

FamilyInfo: The proband was part of a cohort of apparently sporadic cases of pheochromocytoma/ paraganglioma, implying this individual had no family history of VHL disease or pheochromocytoma.

CasePresentingHPOs: HP:0006748 (Adrenal Pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0002668 (Paraganglioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET, SDHB, SDHC, and SDHD

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: ex. p.R161Q (c.482G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: ex. 182983, https://www.ncbi.nlm.nih.gov/clinvar/variation/182983/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R161Q(c.482G>A)

MultipleGeneVariants: N/A

Case#: IV-1, male, 11 y.o, Pakistani

DiseaseAssertion: Limb-girdle muscular dystrophy (LGMD2F), sarcoglycanopathy

FamilyInfo: Consanguineous parents, both described as healthy and showing no abnormality. Three unaffected siblings were also reported: IV-2 (male, 10 y.o), IV-4 (male, 7 y.o), and IV-5 (female, 1.5 y.o). A deceased sister is included on the pedigree, but no details about this individual were reported. See Figure 1.

CasePresentingHPOs: HP:0001288, HP:0002650, HP:0003547, HP:0003749, HP:0001655

CaseHPOFreeText: Reduced weight gain noted at 3-4 y.o. Mild cardiac hypertrophy observed on cardiac review (additional echocardiography results reported in "Echocardiography" section). Additional phenotypic information reported in Supplementary Table 1.

CaseNotHPOs: HP:0009077, HP:0000703, HP:0001382, HP:0000365, HP:0001510, HP:0001249, HP:0000478, HP:0030148, HP:0011675

CaseNotHPOFreeText: Extensor muscles of the wrist, toes flexors, and hip abductors noted to be relatively normal. Additional phenotypic information reported in Supplementary Table 1.

MotorAchievement: Sat without assistance at 8 months of age, walked at 15 months of age, ran at 1.5 months of age. Never jumped or hopped. Frequent falls noted, as well as difficulty in walking and climbing stairs since 3 y.o.

CreatineKinase: 18SU (normal: 20SU for children, 10SU for adults) (see Supplementary Table 1). No assertion was made by the authors regarding whether this represents a normal or decreased CK level.

PreviousTesting: Thyroid stimulating hormone: 2.3mU/L (normal: <0.6mU/L); Serum VZV IgG: 286mlU/ml (normal: >150mlU/ml); IGF-1:186 ng/μl (normal: 102-520 ng/μl for males, 14 y.o); PRL: 202 ng/dl (normal: 42.5-414 ng/dl for males); Vitamin D: 47nmol/L (normal: 25-50 nmol/L); Free T4: 17.0 pmol/L (normal:10.8-19.0 pmol/L) (see Supplementary Table 1)

GenotypingMethod: (1) Targeted next generation sequencing of 31 genes associated with LGMD from proband genomic DNA extracted from peripheral blood sample; (2) Sanger sequencing of genomic DNA extracted from peripheral blood samples to confirm SGCD variant of interest in proband and three family members (III-3, III-4, IV-4). Variant was identified in homozygosity in the proband, in heterozygosity in each of the parents, and was not present in the unaffected sibling (IV-4).

Variant: NM_000337.5:c.289C>T (p.Arg97Ter)

CAID: CA3530549

gnomAD: Not reported