Case:Patient 1, Male, 4 y/o, German and Thai

DiseaseAssertion:FOXG1 syndrome

FamilyInfo: Non-consanguineous parents. De novo. Patient 1 has maternally inherited duplications at 15q21.12(47292250-47309868)x3 and Xp22.31(6451676-8115124)x3 of unknown clinical significance.

ParentalGenotype:Not provided

CasePresentingHPOs:HP:0002197, HP:0005484, HP:0011344, HP:0001252, HP:0020045,HP:0000540, HP:0010808, HP:0002019, HP:0003781, HP:0012741, HP:0002421, HP:0000748, HP:0003763, HP:5200017, HP:0025112, HP:0000957

CaseHPOFreeText: At 19 months, could not sit independently and no speech development. Stereotypic hand and head movements. High pain tolerance. X-ray at age 2 showed broad ribs. Improved head control by age 4.

CaseNotHPO:HP:0410263, HP:0002376

CaseNotHPOFreeText:Dysmorphic features. breathing abnormalities

CasePreviousTesting:No previous testing

PreviouslyPublished:Not previously published

GenotypingMethod:Mate-pair sequencing, Sanger sequencing

Gene:FOXG1

Variant:46,XY,t(9;14)(q22.3;q11.2)dn

HGVS:Not provided

ClinVarID:426096

gnomAD:Not provided

Case:Patient 3, Male, 1 y/o, Brazilian

DiseaseAssertion: FOXG1 syndrome

FamilyInfo: Non-consanguineous parents

ParentalGenotype: No family testing mentioned.

CasePresentingHPOs: HP:0000252, HP:0001252, HP:0000486

CaseHPOFreeText: Developed microcephaly within 1 year. Developmental delay, unable to sit without assistance at 1 year old. Central Nervous System (CNS) MRI showed a volumetric reduction of the cerebral parenchyma, hypomyelination, and hypoplasia of corpus callosum mainly involving the anterior part and prominent lateral ventricles

CaseNotHPO: HP:0030917

CaseNotHPOFreeText: Normal length, weight, HC at birth. No retinal abnormalities.

CasePreviousTesting: Not asserted.

PreviouslyPublished: Not previously published.

GenotypingMethod: Sanger sequencing, mate-pair sequencing

Gene: FOXG1

Variant: 46,XY,t(2;14)(q37;q11.2)dn

HGVS: Not provided.

ClinVarID:426094

gnomAD:Not provided

Case:Patient 2, Female, 5 y/o, Brazilian

DiseaseAssertion:quadriplegic cerebral palsy with axial hypotonia and distal spasticity

FamilyInfo: Non-consanguineous parents. Parents had normal karyotypes. Older sister was clinically normal.

ParentalGenotype: Normal karyotypes for both parents.

CasePresentingHPOs: HP:0002098, HP:0010959, HP:0008755, HP:0002090, HP:0032661, HP:0001274, HP:0011344, HP:0001249, HP:0001344, HP:0000748, HP:0034435, HP:0000486, HP:0000483, HP:0200136

CaseHPOFreeText: Dilated superficial blood vessels seen on brain MRI.

CaseNotHPO:N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Not asserted

PreviouslyPublished: Not previously published

GenotypingMethod:Mate-pair sequencing, Sanger sequencing, chromosome analysis

Gene: FOXG1

Variant: 46,XX,t(4;14)(q27;q13)dn

HGVS: Not provided

ClinVarID: 426095

gnomAD: Not provided

Case#:Patient 52, female, 3 years old

DiseaseAssertion:Neonatal/Infantile Epileptic Encephalopathy (NIEE)

FamilyInfo:DeNovo. The family is Chinese

ParentalGenotype:The authors only conducted singleton and not trio-based exome sequencing so the parents' exomes were not sequenced.

CasePresentingHPOs:HP:0011344, HP:0002069, HP:0007359, HP:0011097, HP:0100704, HP:0001332, HP:0002072, HP:0012171.

CaseHPOFreeText:Patient 52 presents with severe global developmental delay and epilepsy.

Patient 52 has generalized tonic/clonic/tonic-clonic seizures, focal seizures and spasms. Patient 52's seizure onset occurred at 3 months old.

Patient 52 has cortical visual impairment (CVI), dystonia, chorea, and hand-washing sterotypies.

Patient History

@ 3 months - Patient 52 had generalized tonic/clonic/tonic-clonic seizures.

Patient 52 was on 3 antiepileptic drugs at most recent follow-up visit which reduced seizure frequency by >50%.

CaseNotHPOs:Not provided

CaseNotHPOFreeText:Not provided

CasePreviousTesting:The authors selected a cohort of 31 patients with seizure cryptogenic Neonatal/Infantile Epileptic Encephalopathy (NIEE) and seizure onset before 24 months.

Exclusion criteria included: (1) Patients with a definite history of brain insult, malformation of cortical development, neurocutaneous and syndromal disorders, and confirmed or highly suspected neurometabolic disorders based on clinical and biochemical markers. (2) Patients with Dravet syndrome and epilepsy at infancy with migrating focal seizure were also excluded because the majority of variants are detected in the SCN1A (>85%) and KCNT1 (approximately 50%) genes.

Formal neuropsychological testing or best clinical assessment was used to classify patient development or intelligence.

PreviouslyPublished:Not previously published

GenotypingMethod:Whole Exome Sequencing (WES) variant results were filtered in a panel of 430 epilepsy-associated genes. After selection of variants from the 430-gene panel, the synonymous variants, variants with variant frequency <10%, and variants with allele frequency >1% were removed.

Gene:CDKL5

Variant:NM_003159.2 c. 1849delC (p. Arg617Valfs*4)

The authors state that the variant is a heterozygous frameshift deletion.

The authors state that this is a novel variant and is pathogenic.

HGVS:Not provided

ClinVarID:Not found

CAID:Not found.

gnomAD:Not found

MultipleGeneVariants:Not provided

Case: Patient 1, female, 2 years old

DiseaseAssertion: Rett Syndrome

FamilyInfo: DeNovo. Patient 1 was the second child of a nonconsanguineous Chinese couple. Patient 1 was born at full term with a birth weight of 3.83 kg.

ParentalGenotype(s):Not provided

CasePresentingHPOs:HP:0011344, HP:0001250, HP:0001252, HP:0000252, HP:0000748, HP:0003763, HP:0005469, HP:0000486, HP:0012171.

CaseHPOFreeRext:Patient 1 presents with severe global developmental delay, epilepsy, and hypotonia. The Patient History contains all of Patient 1's phenotypes along with the progression of her condition.

Patient History

@ 3 months - Patient 1 had microcephaly (head circumference was less than 3rd percentile with a body weight and body height at 75th percentile). Patient 1 had hypotonia.

Patient 1 was given a metabolic screening, a muscle enzyme, and a brain tomography with normal results.

@ 6 months - Patient 1 had microcephaly, flat occiput, right divergent squint, and hypotonia. No syndromal diagnosis could be ascertained at that time.

@ 2 years - Patient 1 had epilepsy.

Patient 1 had severe global development delay.

Patient 1 was given an EEG which showed nonspecific background slowing, but no epileptiform abnormalities. Patient 1 was also given a brain MRI which showed mild thinning of corpus callosum without major structural defect. Patient 1 had no developmental regression but she developed stereotypical hand movements, bruxism, and occasional outburst of laughter.

Based on these phenotypes, Angelman/Rett Syndrome was suspected.

CaseNOTHPOs: HP:0002353.

CaseNOTHPOFreeText: Patient 1 was given an EEG which detected no epileptic abnormalites.

CasePreviousTesting: Genetic investigations (including methylation-specific multiplex ligation-dependent probe amplification (MS-MLLPA)) was conducted for Angelman Syndrome, UBE3A gene, MECP gene, and array CGH. These studies were negative. A FOXG1 related disease was suspected

PreviouslyPublished:Not previously published

GenotypingMethod: A FOXG1 gene test showed a de novo frameshift pathogenic mutation FOXG1 {NM_005249.3} c. 396_397ins26; FOXG1{NP_005240.3} :(p. Gly133TRPfs*68) which confirmed the diagnosis of a FOXG1 related congenital variant of Rett Syndrome.

Gene:FOXG1

Variant: (NM_005249.3) c. 396_397ins26 (p. Gly133Trpfs*68)

HGVS:Not provided

ClinVarID:Not found

CAID:Not found

gnomAD:Not found

Case:Patient 2, female, Chinese

DiseaseAssertion:Global delay

FamilyInfo:Patient 2 was the first child of nonconsanguineous Chinese couple born at 38-week gestation. The mother had gestational diabetes mellitus that required insulin therapy.

ParentalGenotype:Not provided

CasePresentingHPOs:HP:0000365, HP:0020049, HP:0000252, HP:0001263, HP:0012171, HP:0000154, HP:0000708, HP:0003763, HP:0002376, HP:0012433.

CaseHPOFreeText:

Patient History

@ birth - Patient 2 presented with mild grade bilateral hearing impairment and left divergent squint diagnosed at birth.

@ Follow-up visit - Patient 2 had microbrachycephaly and global developmental delay. Brain MRI, metabolic screening and array CGH were normal.

@ 1 year - Patient 2 had stereotypical handwashing movement.

There was no clinical or electrical seizure.

Patient 2 has craniofacial features like microbrachycephaly, wide mouth, divergent squint, and behavioral phenotype.

@ 1.5 years - Patient 2 had bruxism and developmental regression. Patient 2 also had loss of some motor and social skills.

CaseNotHPOs:HP:0001250

CaseNotHPOFreeText:Patient 2 has no seizures.

CasePreviousTesting:Not provided

PreviouslyPublished:Not previously published

GenotypingMethod:Not provided

Gene:MECP2 (MN_004992.3) (NP_004983.1)

Variant:c. 808C>T (p. Arg270*)

HGVS:Not provided

ClinVarID:Not found

CAID:CA172577

gnomAD:Not found

MultipleGeneVariants:NA

Case:Patient 1, female, 11 years old

DiseaseAssertion:Rett Syndrome - Atypical Variant

FamilyInfo:De Novo. Patient 1's parents were healthy. When Patient 1 was clinically examined, the head circumferences of her mother and father were 53 cm (P25) and 59 cm (P90), respectively. The parents had normal weight.

ParentalGenotype:Both parents were sequenced for Patient 1's mutation, and the deletion was not detected.

CasePresentingHPOs:HP:0001249, HP:0001513, HP:0001626, HP:0000256, HP:0010465, HP:0012758, HP:0000750, HP:0012433, HP:0002591, HP:0001250, HP:0020174, HP:0000316, HP:0000336, HP:0000431, HP:0000377, HP:0000470, HP:0001156, HP:0001500.

CaseHPOFreeText:

Patient history

@ birth - Patient 1 was born at 38 weeks of gestation after an uncomplicated pregnancy. Her weight was 3,390 g (P69), height 51 cm (P60), and her head circumference was 36 cm (P90).

@ 6 months - Patient 1 experienced developmental delay.

@ 9 months - Patient 1 sat without support.

@ 2 years - Patient 1 began to walk.

@ later on - Patient 1 presented with speech delay and behavioral disturbances. The behavioral disturbances were reduced by the drug risperidone.

@ early childhood - Patient 1 has been obese and appeared to display hyperphagia.

@ 8 years - Patient 1 developed precocious puberty.

@ 10 years - Patient 1 had her first epileptic seizure. Treatment with lamotrigine prevented further seizures. The seizures later became refractory to this treatment.

@ 10 years - Patient 1 presented with a height of 160 cm (P>97) and a head circumference of 59 cm (P>97). She had hypertelorism and prominent eyebrows. Her nasal bridge was broad and auricles were fleshy. In addition, Patient 1's neck was short and the fingers were short and wide.

Patient 1 has an intellectual disability, metabolic syndrome, and macrocephaly.

CaseNotHPOs:HP:0002540.

CaseNotHPOFreeText:Patient 1 sat without support at 9 months old. She walked at 2 years.

CasePreviousTesting:Patient 1 was given a conventional cytogenetic analysis. The chromosomal analyses (46,XX) and array CGH results (BlueGnome CytoChip ISCA 4×180K v1.0; Agilent Human Genome CGH Microarray 180K) were normal. Patient 1 was also given a methylation-specific MLPA to exclude a Temple syndrome, which is also characterized by weight gain and precocious puberty. In addition, Prader-Willi syndrome was ruled out by methylation testing. This syndrome is another imprinting disease causing obesity and intellectual disability.

PreviouslyPublished:Not previously published

GenotypingMethod:Whole-exome sequencing analysis of the entire exome was conducted for Patient 1. Whole-genome sequencing showed heterozygosity in Patient 1, which was confirmed by Sanger sequencing. Macrocephalic syndrome genes including PTEN, NSD1, NFIX, SETBP1, RAI1, and PHF6 were analyzed, and no additional variants of interest (pathogenic, likely pathogenic, or variants of uncertain significance) were observed.

Gene:MECP2

Variant:c. 1162_1172del (p. Pro388*), heterozygosity, frameshift.

HGVS:NM_004992.3

ClinVarID:Not found

CAID:CA1139667881

gnomAD:Not found

MultipleGeneVariants:Not provided

Case:Patient 2, female, 2.5 years old

DiseaseAssertion:CDKL5 Disorder

FamilyInfo:De Novo with an unremarkable family history.

ParentalGenotype:Not provided

CasePresentingHPOs:HP:0032792, HP:0007359, HP:0011154, HP:0002194, HP:0010862, HP:0000750, HP:0012434, HP:0000710, HP:0100023, HP:0000252, HP:0009062, HP:0010845, HP:0020174, HP:0010841.

CaseHPOFreeText:

Patient history

@ 2 months to 2.5 years - Patient 2 experienced tonic and focal seizures with autonomic symptoms.

@ 2 years - Patient 2 was diagnosed with CDKL5 disorder.

Patient 2 had severe delayed gross motor development, severe delayed fine motor development, severe delayed language development and delayed social development. Patient 2 had hyperoral and hand flapping stereotypies. She also had microcephaly (< 2 SD) and axial hypotonia.

Patient 2 was given a brain EEG which detected Delta slowing of the background followed by generalized attenuation during seizures and multifocal interictal epileptiform abnormalities.

@ 2.5 years - Patient 2 experienced seizures in clusters.

Treatments

Antiepleptic treatments included:Phenobarbital, Topirimate, Clobazam, Valproate, Keppra, Vitamin B6, Phenytoin, Lamotrigine, Nitrazepam, Oxcarbazepine, Mirtazipine, KCI, Levetiracetam, ant ketogenic diet.

Patient 2 was also treated with Carnitine. Patient 2's seizures seem to have changed in type over time but continued.

Other testing

Tests were conducted on Patient 2 to obtain data in the following areas: NBS, lactate, lipoprotein profile, plasma and urine amino acids, urine organic acids, acylcarnitine profile, total and free serum carnitine levels, plasma ammonia, total plasma homocysteine, serum CK, liver enzymes, urine alpha-AASA, creatine, biotinidase, VLCFA, Batten disease screen, CSF analysis (amino acids, lactate, glucose, protein, cell count, neurotransmitters), MRI-brain with spectroscopy, and karyotype.

CaseNotHPOs:Not provided

CaseNotHPOFreeText:Not provided

CasePreviousTesting:Patient 2 was given a gene sequence test for the genes SCNIA and MECP2. No gene mutation was found for these two genes.

PreviouslyPublished:Not previously published

GenotypingMethod:Patient 2 was given a CDKL5 gene sequence test. The test detected a mutation in the CDKL5 gene.

Gene:CDKL5

Variant:c. 2480_2486dupCAGATCT. frameshift

The authors state that CDKL5 gene sequencing detected a de novo duplication in exon 17, c. 2480_2486dupCAGATCT, resulting in a frameshift (Boston University School of Medicine, Center for Human Genetics, Boston, MA). This is a novel change that has not been reported before in ExAC. Only pathogenic point mutations in exon 17 have previously been reported. In a patient with a previously reported frameshift mutation in exon 18, a truncated CDKL5 transcript was detected. A truncated protein would lack the C-terminus and would not localize correctly in the cell, as demonstrated in vitro. Accordingly, any reading frame altering mutations proximal to exon 18 are null-variants. Therefore, this mutation is classified as pathogenic according to ACMG criteria.

HGVS:Not provided

ClinVarID:547188

NM_001323289.2 (CDKL5): c. 2480_2486dup (p. Gln830fs)

Allele ID: 538303

CAID:Not found

gnomAD:Not found

MultipleGeneVariants:Not provided

Case#: case_Kiyota_2018, female,1 yo (onset), Japanese ancestry reported

DiseaseAssertion: APDS + 22q13 deletion syndrome

FamilyInfo: de novo

CasePresentingHPOs: (HP:0001973, HP:0000969, HP:0011134, HP:0000123, HP:0000093, HP:0003073, HP:0004431, HP:0003493, HP:0020151, HP:0033604, HP:0001263, HP:0001290, HP:0000729, HP:0002463, HP:0001249, HP:0007021, HP:0012433

ITP systemic edema mild fever lupus nephritis proteinuria hypoalbuminemia decreased complement levels antinuclear antibody double strand DNA antibody wire-loop lesions in glomeruli delayed psychmotor development hypotonia autistic features language delay intellectual disability reduced sensitivity to pain poor social functioning

CaseHPOFreeText: positive staining for IgG, IgA, IgM, C3 and C1q and electron-dense deposits observed through renal biopsy, along with wire-loop lesions

CaseNotHPOs: (HP:0030882, 0010783, HP:0030880) coronary aneurysm butterfly erythema Raynaud's phenomenon

CaseNotHPOFreeText: dysmorphic features

CasePreviousTesting: G-band karyotyping + whole genome SNP microarray revealed 22q13 deletion syndrome

GenotypingMethod: WES

PreviouslyPublished:

Variant: NM_005026.3:c.1534C > T; p.(Arg512Trp)

ClinVarID: 1347382

CAID: CA577258

gnomAD: v2.1.1 Grpmax 0.00007392 (4/18252 alleles) East Asian population

SupplementalData:

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#: Hui_2016, female, 2 yo (presentation), origin NR

DiseaseAssertion: APDS

FamilyInfo: variants verified in patient's parents, found to be de novo. It is unclear if case 2 and case 4 are related or unrelated.

CasePresentingHPOs: recurrent respiratory infections, enlargement of lymph node, hepatosplenomegaly, decreased number of native CD4 + T cells, inverted CD4 + /CD8 + T cell ratio and increased IgM, decreased IgA, decreased IgG,

HP:0002205, HP:0002716, HP:0001433, HP:0002720, HP:0032218, HP:0033222, HP:0002720, HP:0003496

CaseHPOFreeText: cytomegalovirus (CMV) or Epstein-Barr virus (EBV) viremia

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

CasePreviousTesting: NR

GenotypingMethod: WGS

PreviouslyPublished: NR

Variant: HOMOZYGOUS 3061G>A (E1021K)

ClinVarID: 88675

CAID: N/A

gnomAD: not found in v2.1.1

SupplementalData: unknown

Note: Full access to article denied. Info in annotation gathered from abstract. Also, please be advised the curator translated the article from Chinese to English, and mistranslations are possible.

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.