PMID: 37600808

Gene: PIK3CD Gene: PIK3R1

HGNC: 8977 HGNC: 8979

Case#: 2-month-old boy

DiseaseAssertion:

FamilyInfo: One healhy brother, noncontributory

CasePresentingHPOs: HP:0025104(Capillary malformation) HP:0004691(2-3 toe syndactyly) HP:0001520(Large for gestational age) HP:0001548(Overgrowth) HP:0033725(Thin corpus callosum) HP:0004315(Decreased circulating IgG level) HP:0002720(Decreased circulating IgA level)

CaseHPOFreeText: At 12 months of age two ear infections occuring four weeks apart and a bilateral eye infection.

CaseNotHPOs: HP:0012759(Neurodevelopmental abnormality) HP:0002850(Decreased circulating total IgM)

CaseNotHPOFreeText: Segmental overgrowth was not observed. Normal newborn bloodspot and hearing screen. Ophthalmology examination is normal. No no evidence for a capillary pial vascular malformation

CasePreviousTesting: Whole-exome sequencing and mtDNA testing

GenotypingMethod: Exome sequencing and mtDNA testing was performed on the patient’s blood sample and cultured fibroblast from a 3 mm punch biopsy from right lower paraspinal region.

PreviouslyPublished: No

Variant: NM_181523.2:c.1746-2A>G p.? 9% of the proband's blood cells (74 sequencing reads) and in 25% of the cultured fibroblasts (84 sequencing reads).

ClinVar: https://www.ncbi.nlm.nih.gov/clinvar/variation/1298995/ germline

CAID: CA359883172

gnomAD: Not present in gnomAD

Case#: 6‐year‐old Japanese female

DiseaseAssertion: Patients are asserted to have “SHORT syndrome” and “harbor either a common or a previously unknown mutation in PIK3R1 as well as provide an in silico functional analysis of the mutant proteins.”

FamilyInfo: No relevant family history

CasePresentingHPOs: HP:0001511, HP:0000855, HP:0004322, HP:0000490, HP:0000684, HP:0000325, HP:0000430, HP:0000400, HP:0000369, HP:0005328, HP:0000545, HP:0000963, HP:0007392, HP:0000365

CaseHPOFreeText: Born with a birth length of 43.1 cm (−1.3 SD relative to the average for this gestational age) and birth weight of 1,544 g (−2.7 SD relative to the average for this gestational age). Her height was 104.0 cm and weight 12.6 kg at the time of evaluation for this study, indicating no apparent short stature (−1.0 SD relative to the average for this age). Her fasting plasma glucose, serum IRI concentrations, and serum C‐peptide were 108 mg/dL, 56.4 μIU/mL, and 6.95 ng/mL, respectively, with an HbA1c level of 5.2%. Her HOMA‐IR was 15.0, and her HOMA‐β was 451.2%. She had a hearing threshold of 30 and 50 dB in the right and left ears, respectively. Otitis media was apparent in the right ear, but not in the left. Patient had readily visible veins.

CaseNotHPOs: HP:0000819, HP:0001382, HP:0000023, HP:0011220, HP:0000331, HP:0000233, HP:0002714, HP:0000540, HP:0000483, HP:0000593, HP:0000501, HP:0100578, HP:0001249, HP:0000750

CaseNotHPOFreeText: N/A

CasePreviousTesting: NR

GenotypingMethod: Initially, comprehensive sequencing analysis was conducted on all 22 exons of the INSR gene using the Sanger sequencing method, confirming the absence of pathogenic variants. Subsequently, sequencing was extended to encompass all 16 exons of the PIK3R1 gene.

PreviouslyPublished: No

Variant: NM_181523.3:c.1945C>T

ClinVar: 60763

gnomAD: NR

SupplementalData: Table 1, Figure 1a,b

Case#: 33-year‐old Japanese male

DiseaseAssertion: Patients are asserted to have “SHORT syndrome” and “harbor either a common or a previously unknown mutation in PIK3R1 as well as provide an in silico functional analysis of the mutant proteins.”

FamilyInfo: His daughter has SHORT syndrome, with the same variant of PIK3R1, NM_181523.3:c.1957A>T, further described in Case 3. His mother also manifests some facial characteristics of SHORT syndrome as well as a hearing impairment.

CasePresentingHPOs: HP:0008619, HP:0000365, HP:0000501, HP:0000819, HP:0001511, HP:0004322, HP:0000023, HP:0000490, HP:0000558, HP:0000325, HP:0011220, HP:0000430, HP:0000331, HP:0000400, HP:0005328, HP:0100578

CaseHPOFreeText: He was born at 36 weeks of gestation with a birth weight of 1,970 g. Weight at time of diagnosis was 44.2 kg (-2.4 SD), height 154 cm (-3.00SD) , body mass index 18.6 kg/m2 (-1.5 SD). He had been treated with a DPP‐IV (dipeptidyl peptidase‐IV) inhibitor and an SGLT2 inhibitor and manifesting an HbA1c level of 7.4% at the time of the current evaluation. His blood glucose and serum IRI levels at baseline and at 30, 60, 90, and 120 min after the glucose load were 130, 220, 238, 243, and 252 mg/dL and 8.0, 15.5, 25.6, 27.1, and 24.6 μIU/mL, respectively. His HOMA‐IR, HOMA‐β, and insulinogenic index were 2.57, 43.0%, and 0.083, respectively.

CaseNotHPOs: HP:0000855, HP:0001382, HP:0000684, HP:0000369, HP:0000233, HP:0002714, HP:0000540, HP:0000483, HP:0000545, HP:0000593, HP:0000963, HP:0007392, HP:0001249, HP:0000750

CaseNotHPOFreeText: Readily visible veins

CasePreviousTesting: NR

GenotypingMethod: Initially, comprehensive sequencing analysis was conducted on all 22 exons of the INSR gene using the Sanger sequencing method, confirming the absence of pathogenic variants. Subsequently, sequencing was extended to encompass all 16 exons of the PIK3R1 gene.

PreviouslyPublished: No

Variant: NM_181523.3:c.1957A>T

ClinVar: 3767319

gnomAD: NR

SupplementalData: Table 1, Figure 1e,f

Case#: 15-year-old boy

DiseaseAssertion: SHORT syndrome and Immunodeficiency 36

FamilyInfo: Table2 Father is wild type, mother was unavailable for testing. Consanguinity was reported at Table 4. No affected family members Table4.

CasePresentingHPOs: HP:0001511(Intrauterine growth retardation) HP:0004322(Short stature) HP:0000325(Triangular face) HP:0010751(Dimple chin) HP:0000684(Delayed eruption of teeth) HP:0000347(micrognathia) HP:0100750(Atelectasis) HP:0004469(chronic bronchitis) HP:0002110(bronchiectasis) HP:0002720(Decreased circulating IgA level) HP:0011342(Mild global developmental delay) HP:0004279(short hands) HP:0000954(Single transverse palmar crease) HP:0002205(Recurrent respiratory infections)

CaseHPOFreeText:

CaseNotHPOs: Height -5.5 to -6.1 SDS

CaseNotHPOFreeText: N/A

CasePreviousTesting: CMA and MS-MLPA for chromosomes 6,14,20 was performed.

GenotypingMethod: Whole-exome sequencing was performed on the patient’s whole blood sample.

PreviouslyPublished: No

Variant: NM_001242466.2:c.68G > A p.Arg23Gln

ClinVar: 1361868

CAID: CA3290343

gnomAD: 0.00005439 https://gnomad.broadinstitute.org/variant/5-67589169-G-A

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.

PMID: 39044864 Gene: PIK3R1 HGNC: 8979