Case#: Female, age of onset: 13, age at testing: 32, age of last documented clinical stability: 34

DiseaseAssertion: suspected hypoactivation of the PI3K pathway

FamilyInfo: maternal grandmother with rheumatoid arthritis, eldest sister died at 4 months due to septic shock after enteritiis

CasePresentingHPOs: HP:0002028, HP:0001945, HP:0025085, HP:0100279, HP:0002090, HP:0012388, HP:0033256, HP:0004313 (recurrent diarrhea, fever, bloody diarrhea, ulcerative colitis (UC), pneumonia, and multiple episodes of acute bronchitis, pancolitis due to Clostridioides difficile infection, hypogammaglobulinemia)

CaseHPOFreeText: salmonellosis, psoriasis and psoriatic arthropathy affecting large joints, reduced B-cell compartment, bronchiectasis suggestive of CVID, unresponsive vaccination test, esophageal dysphagia, neutrophilic esophagitis

CaseNotHPOs: HP:0001249 (intellectual disability)

CaseNotHPOFreeText: dysmorphic features, patient has normal psychomotor and cognitive development,

CasePreviousTesting: clinical exome sequencing

GenotypingMethod: sequencing

PreviouslyPublished: No prior article is known to contain information on the same proband.

Variant: NM_005026.5(PIK3CD): [c.2608C > T (p.Arg870)] ; [c.2608C > T (p.Arg870)]

ClinVar: not

CAID:CA338307789

gnomAD: 0.0003%

SupplementalData: There is no supplemental data, clinical timeline and schematic with noted variants are in Figure 2 and Figure 3

Case#: P3, 9-years-old Saudi girl

CasePresentingHPOs: HP:0002028, HP:0005425, HP:0100281

CaseHPOFreeText: P3 is a 9 years old girl with history of chronic diarrhea and recurrent sinopulmonary infections since the age of 4 months. Immunological evaluation at age of 3 years showed normal complete blood counts and differential, lymphocytes subsets, lymphocytes proliferation and oxidative burst assays. Her IgG level was 3.1 gm/L with normal IgA and IgM levels and her antibody response to pneumococcal polysaccharide vaccine could not be well assessed as she received conjugated pneumococcal vaccines (Table 1). Her recurrent chest infections improved after starting intravenous immunoglobulins. Upper and lower endoscopies showed architectural distortion with focal cryptitis from cecum, ascending and transverse colon biopsies and severe active chronic colitis with crypt abscesses and ulcerations from sigmoid and rectal biopsies with no viral cytopathic changes or granuloma. Her diarrhea was treated mainly with sulfasalazine therapy. Her weight and height are normal in spite of her chronic diarrhea.

Variant: NM_005026.4: c.433delinsGA: p.Q145Efs*51

GenotypingMethod: DNA from all individuals we had access to was submitted for whole-genome genotyping, to determine regions of autozygosity that are shared between all affecteds. This was done under the assumption of an autosomal recessive inheritance pattern, given the nature of the pedigree and the presence of parental consanguinity. Three such regions were highlighted by the software, of which the largest was a 12.3 Mb block on Chr 1 (Fig. 1B). Simultaneously we submitted the DNA from patient P1 for WES, and followed the NGS filtering scheme indicated in Fig. 1C. Once we had limited our search area to the regions of shared autozygosity which were exclusive to the three patients, no variants survived our filtering except for one

CAID: CA3252646241

**Case#: ** P1, 19-years-old Saudi male

**DiseaseAssertion: ** P1 is asserted to have "Crohn disease" and "CMV gastritis"

CasePresentingHPOs: HP:0002028, HP:0005425, HP:0000964, HP:0011473, HP:0200120

CaseHPOFreeText: P1 is a 19 year old boy with history of chronic diarrhea, recurrent sinopulmonary infections and dermatitis since the age of 2 months. At age of 1 year full upper and lower endoscopy showed duodenal villous atrophy and mild duodenitis, and antrum biopsy was suggestive of CMV gastritis with no significant colon biopsy findings. At 13 years of age he was evaluated by immunology service to rule out IEI. His complete blood counts and differential, lymphocytes subsets, lymphocytes proliferation and oxidative burst assays were normal. His IgG level was subnormal for age (4.2 gm/L) with undetectable IgM levels (Table 1). He was started on intravenous immunoglobulins with good clinical response in regard to his recurrent sinopulmonary infections. He continued to have chronic diarrhea that on frequent occasions was bloody, but he had normal weight gain and growth. Upper and lower endoscopies were performed on several occasions and showed severe chronic active colitis with ulcerations, epithelial reactive changes with granulomatous tissue formation suggestive of Crohn disease. His diarrhea responded partially to sulfasalazine therapy and short courses of steroids.

Variant: NM_005026.4: c.433delinsGA: p.Q145Efs*51

GenotypingMethod: DNA from all individuals we had access to was submitted for whole-genome genotyping, to determine regions of autozygosity that are shared between all affecteds. This was done under the assumption of an autosomal recessive inheritance pattern, given the nature of the pedigree and the presence of parental consanguinity. Three such regions were highlighted by the software, of which the largest was a 12.3 Mb block on Chr 1 (Fig. 1B). Simultaneously we submitted the DNA from patient P1 for WES, and followed the NGS filtering scheme indicated in Fig. 1C. Once we had limited our search area to the regions of shared autozygosity which were exclusive to the three patients, no variants survived our filtering except for one

CAID: CA3252646241

Case#: P2, 18-years-old Saudi girl

DiseaseAssertion: P1 is asserted to have "eosinophilic colitis"

CasePresentingHPOs: HP:0002028, HP:0005425, HP:0000964

CaseHPOFreeText: P2 is an 18 years old girl with history of chronic diarrhea, recurrent sinopulmonary infections and dermatitis since the age of 5 months. Immunological evaluation at age of 12 years showed normal complete blood counts and differential, lymphocytes subsets, lymphocytes proliferation and oxidative burst assays. Her IgG level was subnormal for age (3.6 gm/L) with undetectable IgM levels and poor antibody response to pneumococcal polysaccharide vaccine (Table 1). Her recurrent chest infections improved after starting intravenous immunoglobulins. She continued to have chronic diarrhea that was frequently bloody, but she also maintained normal weight gain and growth. Upper and lower endoscopies showed colonic heavy infiltration by eosinophils and focal eosinophilic abscesses consistent with eosinophilic colitis. Similar to her brother, the diarrhea responded partially to sulfasalazine therapy and short courses of steroids.

Variant: NM_005026.4: c.433delinsGA: p.Q145Efs*51

GenotypingMethod: DNA from all individuals we had access to was submitted for whole-genome genotyping, to determine regions of autozygosity that are shared between all affecteds. This was done under the assumption of an autosomal recessive inheritance pattern, given the nature of the pedigree and the presence of parental consanguinity. Three such regions were highlighted by the software, of which the largest was a 12.3 Mb block on Chr 1 (Fig. 1B). Simultaneously we submitted the DNA from patient P1 for WES, and followed the NGS filtering scheme indicated in Fig. 1C. Once we had limited our search area to the regions of shared autozygosity which were exclusive to the three patients, no variants survived our filtering except for one

CAID: CA3252646241

Case#: 10 years old

DiseaseAssertion:See Table 1

FamilyInfo: Not Mentioned

CasePresentingHPOs: Not specified

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/a

CasePreviousTesting: See Table 2

Variant: NM_000350.3(ABCA4):c.4139C>T (p.Pro1380Leu)

ClinVar: 7904 https://www.ncbi.nlm.nih.gov/clinvar/variation/7904/

CAID: CA129033

gnomAD: 0.00030430 https://gnomad.broadinstitute.org/variant/chr1-94031110-G-A?dataset=gnomad_r4

SupplementalData: Table 2

Case#: Age is not specified (Age of onset: 15 years old, with the time from onset: 8 years)

DiseaseAssertion: Presented with macular flecks and alterations in the retinal pigment epithelium (RPE) subretinal deposits.

FamilyInfo: Consanguinity within the family

CasePresentingHPOs: HP:0000608, HP:0008035 (Macular Degeneration, Retinis pigmentosa inversa)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: Visual Acuity: 20/20

CasePreviousTesting: See Table 2

Variant: NM_000350.3(ABCA4):C.4793C>A (p.Ala1598Asp)

ClinVar: 99321 https://www.ncbi.nlm.nih.gov/clinvar/variation/99321/

CAID: CA227239

gnomAD: 0.00002631 https://gnomad.broadinstitute.org/variant/1-94021695-G-T?dataset=gnomad_r3

SupplementalData: Table 2, Results Section

Case#: male, onset at or before age 12 months, ethnicity not specified DiseaseAssertion: Patient is asserted to have both "SHORT syndrome" and "X-linked agammaglobulinemia (XLA)" due to "absence of peripheral B cells" and "features of SHORT syndrome such as hyperextensibility, vision abnormalities, lack of fat tissue, triangular face, extroverted ears, ocular depression, [and] developmental and teething delay" CasePresentingHPOs: HP:0000974 (Hyperextensible skin), HP:0000504 (Abnormality of vision), HP:0005320 (Lack of facial subcutaneous fat), HP:0000325 (Triangular face), HP:0000430 (Underdeveloped nasal alae), HP:0000490 (Deeply set eye), HP:0000750 (Delayed speech and language development), HP:0002719 (Recurrent infections), HP:0030084 (Clinodactyly), HP:0045075 (Sparse eyebrow), HP:0000540 (Hypermetropia), HP:0000696 (Delayed eruption of permanent teeth) CaseHPOFreeText: A current 9 year old was diagnosed with XLA with SHORT at age 15 months after presenting with skin lesions, scrotal swelling and ulcers along with recurring upper and lower tract infections after 6 months of age. Evaluations for immunodeficiencies were performed. Basic immunoglobulin levels and lymphocyte subsets were measured, which suggested an XLA diagnosis. Delays in developmental milestones observed by the mother and physical examination suggested SHORT syndrome. CaseNotHPOs: HP:0000558 (Rieger anomaly), HP:0000364 (Hearing abnormality) GenotypingMethod: Genotyping was performed by whole exome sequencing, whivh revealed a novel pathogenic homozygous frameshift mutation in the PIK3R1 gene. PreviouslyPublished: No prior article is known to contain information on the same proband. Variant: The patient harbors NM_181523.3:c.244dup(p.(lle82Asnfs24) chr5:67522740) variant in the homozygous state. ClinVar: This variant was not found in ClinVar CAID: This variant was not found in the ClinGen Allele Registry. gnomAD:* The variant was not found in gnomAD v4.1.0.

Case#: 36 y.o male European

DiseaseAssertion: Limb Girdle

FamilyInfo: None

CasePresentingHPOs: HP:0003701,HP:0003560, HP:0006785, HP:0003236,HP:0003325, HP:0008981,

CaseHPOFreeText: Experienced two episodes of atrial fibrillation. High CADD scores. Exercise-induced myalgia and/or rhabdomyolysis

CaseNotHPOs:

CaseNotHPOFreeText:

MotorAchievement: Age 20 he developed exercise intolerance and sporadic myoglobinuria after intense exercise. Able to walk and cycle for long distances with little muscle pain.

CreatineKinase: Ranging from 1700 to 8000 UI/L), at the age of 10 years

CasePreviousTesting: Last neurological examination there was moderate calf hypertrophy.

GenotypingMethod: Muscle Biopsy using next generation sequencing and multiple gene panel. Minimal myopathic changes on histological assessment and normal immunofluorescence staining for muscle proteins including α-sarcoglycan

PreviouslyPublished:

Variant: NM_000023.4(SGCA):c.850C>T (p.Arg284Cys)

ClinVar: 9439

CAID:

gnomAD: 0.0007716