PMID: 37758162

Gene: PIK3R1

HGNC: 8979

Article ID

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.

PIK3CD (p.Glu525Gly)

PMID:38485815

Gene:CTLA4

HGNC:2505

PMID:38634985

Gene:PIK3CD

HGNC:8977

Case#: P1, M, Age of Report: N/A, Ethnicity: N/A.

CasePresentingHPOs: HP:0000490 (Deeply set eye/Ocular depression), HP:0000680 (Delayed eruption of primary teeth/Teeth delay), HP:0000540 (Hypermetropia/Hyperopia), HP:0000483 (Astigmatism), HP:0007485 (Absence of subcutaneous fat/Lack of subcutaneous fat), HP:0000831 (Insulin-resistant diabetes mellitus), HP:0000325 (Triangular face/Facial dysmorphim Triangular shape), HP:0000430 (Underdeveloped nasal alae/thin alae nasi), HP:0000331 (Short chin/Small chin), HP:0000369 (Low-set ears), HP:0012371 (Hyperplasia of midface/Mild midface hypoplasia), HP:0000347 (Micrognathia), HP:0100678 (Premature skin wrinkling/Thin, wrinkled skin), HP:0001256 (Intellectual disability, mild/Mild impairment),

CaseHPOFreeText: Proband was noted to have readily visible veins and delayed bone age.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WES.

Variant: NM_181523.3:c.1615_1617del (p.Ile539del).

ClinVar: 60761.

CAID: CA344796.

gnomAD: N/A.

VariantEvidence: N/A.

CaseAddInfo: N/A.

CasePMIDs: N/A.

Case#: P2, M, Age of Report: N/A, Ethnicity: N/A.

CasePresentingHPOs: HP:0000490 (Deeply set eye/Ocular depression), HP:0000680 (Delayed eruption of primary teeth/Teeth delay), HP:0007485 (Absence of subcutaneous fat/Lack of subcutaneous fat), HP:0000831 (Insulin-resistant diabetes mellitus), HP:0000325 (Triangular face/Facial dysmorphim Triangular shape), HP:0000430 (Underdeveloped nasal alae/thin alae nasi), HP:0000331 (Short chin/Small chin), HP:0000369 (Low-set ears), HP:0012371 (Hyperplasia of midface/Mild midface hypoplasia), HP:0000347 (Micrognathia), HP:0100678 (Premature skin wrinkling/Thin, wrinkled skin), HP:0001256 (Intellectual disability, mild/Mild impairment),

CaseHPOFreeText: Proband was noted to have readily visible veins and delayed bone age.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A..

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WES.

Variant: NM_181523.3:c.1465G>A (p.Glu489Lys).

ClinVar: 60762.

CAID: CA344798.

gnomAD: N/A.

VariantEvidence: N/A.

CaseAddInfo: N/A.

CasePMIDs: N/A.

Case#: P3, F, Age of Report: N/A, Ethnicity: N/A.

CasePresentingHPOs: HP:0001382 (Joint hypermobility/Hyperextensibility of joints), HP:0000490 (Deeply set eye/Ocular depression), HP:0000558 (Rieger anomaly), HP:0000680 (Delayed eruption of primary teeth/Teeth delay), HP:0000540 (Hypermetropia/Hyperopia), HP:0000483 (Astigmatism), HP:0000565 (Esotropia), HP:0007485 (Absence of subcutaneous fat/Lack of subcutaneous fat), HP:0000831 (Insulin-resistant diabetes mellitus), HP:0000325 (Triangular face/Facial dysmorphim Triangular shape), HP:0011220 (Prominent forehead), HP:0000430 (Underdeveloped nasal alae/thin alae nasi), HP:0000331 (Short chin/Small chin), HP:0000369 (Low-set ears), HP:0012371 (Hyperplasia of midface/Mild midface hypoplasia), HP:0000347 (Micrognathia), HP:0000138 (Ovarian cyst), HP:0001256 (Intellectual disability, mild/Mild impairment), HP:0003100 (Slender long bone/Gracile long bones)

CaseHPOFreeText: Proband was noted to have delayed bone age and mild impairment and/or speech delay

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A..

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WES.

Variant: NM_181523.3:c.1945C>T (p.Arg649Trp).

ClinVar: 60763.

CAID: CA344799.

gnomAD: N/A.

VariantEvidence: N/A.

CaseAddInfo: N/A.

CasePMIDs: N/A.

Case#: P4, M, Age of Report: N/A, Ethnicity: N/A.

CasePresentingHPOs: HP:0004322 (Short stature), HP:0004325 (Decreased body weight), HP:0040195 (Decreased head circumference), HP:0000490 (Deeply set eye/Ocular depression), HP:0000680 (Delayed eruption of primary teeth/Teeth delay), HP:0000540 (Hypermetropia/Hyperopia), HP:0007485 (Absence of subcutaneous fat/Lack of subcutaneous fat), HP:0000325 (Triangular face/Facial dysmorphim Triangular shape), HP:0011220 (Prominent forehead), HP:0000430 (Underdeveloped nasal alae/thin alae nasi), HP:0000331 (Short chin/Small chin), HP:0000369 (Low-set ears), HP:0012371 (Hyperplasia of midface/Mild midface hypoplasia), HP:0000347 (Micrognathia), HP:0100678 (Premature skin wrinkling/Thin, wrinkled skin),

CaseHPOFreeText: Proband was noted to readily visible veins, normal mental development.

Proband was not evaluated for insulin resistance, ovarian cysts, delayed bone age or gracile long bones.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: Proband was noted to not have hyperextensibility of joints, inguinal hernia, Rieger anomaly, astigmatism, myopia, esotropia, diabetes, frequent illnesses, mild impairment and/or speech delay.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WES.

Variant: NM_181523.3:c.1945C>T (p.Arg649Trp).

ClinVar: 60763.

CAID: CA344799.

gnomAD: N/A.

VariantEvidence: N/A.

CaseAddInfo: N/A.

CasePMIDs: N/A.

Case#: P5, F, Age of Report: N/A, Ethnicity: N/A.

CasePresentingHPOs: HP:0001382 (Joint hypermobility/Hyperextensibility of joints), HP:0000490 (Deeply set eye/Ocular depression), HP:0000558 (Rieger anomaly), HP:0000680 (Delayed eruption of primary teeth/Teeth delay), HP:0000545 (Myopia), HP:0007485 (Absence of subcutaneous fat/Lack of subcutaneous fat), HP:0000831 (Insulin-resistant diabetes mellitus), HP:0000325 (Triangular face/Facial dysmorphim Triangular shape), HP:0011220 (Prominent forehead), HP:0000430 (Underdeveloped nasal alae/thin alae nasi), HP:0000331 (Short chin/Small chin), HP:0000369 (Low-set ears), HP:0012371 (Hyperplasia of midface/Mild midface hypoplasia), HP:0000347 (Micrognathia),

CaseHPOFreeText: Proband was noted to have insulin resistance, frequent illnesses, ovarian cysts, normal mental development,

Proband was not evaluated for delayed bone age or gracile long bones.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: Proband was noted to not have inguinal hernia, hyperopia, astigmatism, esotropia, thin, wrinkled skin, readily visible veins, mild impairment and/or speech delay.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WES.

Variant: NM_181523.3:c.1945C>T (p.Arg649Trp).

ClinVar: 60763.

CAID: CA344799.

gnomAD: N/A.

VariantEvidence: N/A.

CaseAddInfo: N/A.

CasePMIDs: N/A.

Case#: P6, M, Age of Report: N/A, Ethnicity: N/A.

CasePresentingHPOs: HP:0000490 (Deeply set eye/Ocular depression), HP:0000325 (Triangular face/Facial dysmorphim Triangular shape), HP:0011220 (Prominent forehead), HP:0000430 (Underdeveloped nasal alae/thin alae nasi), HP:0000331 (Short chin/Small chin), HP:0000369 (Low-set ears), HP:0012371 (Hyperplasia of midface/Mild midface hypoplasia), (Micrognathia),

CaseHPOFreeText: Proband was not evaluated for inguinal hernia, Rieger anomaly, teeth delay, hyperopia, astigmatism, myopia, esotropia, lack of subcutaneous fat, insulin resistance, diabetes, thin, wrinkled skin, readily visible veins, frequent illnesses, ovarian cysts, normal mental development, mild impairment and/or speech delay, delayed bone age or gracile long bones.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: Proband was noted to not have hyperextensibility of joints,

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WES.

Variant: NM_181523.3:c.1945C>T (p.Arg649Trp).

ClinVar: 60763.

CAID: CA344799.

gnomAD: N/A.

VariantEvidence: N/A.

CaseAddInfo: N/A.

CasePMIDs: N/A.

Case#: P7, F, Age of Report: N/A, Ethnicity: N/A.

CasePresentingHPOs: HP:0000680 (Delayed eruption of primary teeth/Teeth delay), HP:0000483 (Astigmatism), HP:0007485 (Absence of subcutaneous fat/Lack of subcutaneous fat), HP:0000831 (Insulin-resistant diabetes mellitus), HP:0011220 (Prominent forehead), HP:0000430 (Underdeveloped nasal alae/thin alae nasi), HP:0000331 (Short chin/Small chin), HP:0000369 (Low-set ears), HP:0000347 (Micrognathia),

CaseHPOFreeText: : Proband was noted to have insulin resistance, ovarian cysts, normal mental development,

Proband was not evaluated for hyperextensibility of joints, ocular depression, hyperopia, myopia, esotropia, Triangular face, Mild midface hypoplasia, frequent illnesses, delayed bone age or gracile long bones.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: Proband was noted to not have inguinal hernia, Rieger anomaly, thin, wrinkled skin, readily visible veins, mild impairment and/or speech delay,

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WES.

Variant: NM_181523.3:c.1945C>T (p.Arg649Trp).

ClinVar: 60763.

CAID: CA344799.

gnomAD: N/A.

VariantEvidence: N/A.

CaseAddInfo: N/A.

CasePMIDs: N/A.

Case#: P8, F, Age of Report: N/A, Ethnicity: N/A.

CasePresentingHPOs: HP:0007485 (Absence of subcutaneous fat/Lack of subcutaneous fat), HP:0000831 (Insulin-resistant diabetes mellitus), HP:0000325 (Triangular face/Facial dysmorphim Triangular shape), HP:0011220 (Prominent forehead), HP:0000430 (Underdeveloped nasal alae/thin alae nasi), HP:0000331 (Short chin/Small chin), HP:0000369 (Low-set ears), HP:0012371 (Hyperplasia of midface/Mild midface hypoplasia), HP:0000347 (Micrognathia),

CaseHPOFreeText: Proband was noted to have insulin resistance, thin, wrinkled skin, readily visible veins, frequent illnesses, normal mental development,

Proband was not evaluated for hyperextensibility of joints, teeth delay, hyperopia, astigmatism, myopia, esotropia, ovarian cysts, delayed bone age or gracile long bones.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: Proband was noted to not have inguinal hernia, Rieger anomaly, mild impairment and/or speech delay.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WES.

Variant: NM_181523.3:c.1943dup (p.Arg649ProfsTer5).

ClinVar: 60764.

CAID: CA344800.

gnomAD: N/A.

VariantEvidence: N/A.

CaseAddInfo: N/A.

CasePMIDs: N/A.

Case#: P9, M, Age of Report: N/A, Ethnicity: N/A.

CasePresentingHPOs: HP:0004325 (Decreased body weight), HP:0007485 (Absence of subcutaneous fat/Lack of subcutaneous fat), HP:0000831 (Insulin-resistant diabetes mellitus), HP:0000325 (Triangular face/Facial dysmorphim Triangular shape), HP:0000430 (Underdeveloped nasal alae/thin alae nasi), HP:0000331 (Short chin/Small chin), HP:0000369 (Low-set ears), HP:0000347 (Micrognathia),

CaseHPOFreeText: Proband was noted to have insulin resistance, normal mental development, mild impairment and/or speech delay,

Proband was not evaluated for height/length, occipitofrontal circumference, hyperextensibility of joints, teeth delay, hyperopia, astigmatism, myopia, esotropia, thin, wrinkled skin, readily visible veins, frequent illnesses, ovarian cysts, delayed bone age or gracile long bones.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: Proband was noted to not have inguinal hernia, ocular depression, Rieger anomaly, Prominent forehead, Mild midface hypoplasia,

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WES.

Variant: NM_181523.3:c.1892G>A (p.Arg631Gln).

ClinVar: 126459.

CAID: CA347796.

gnomAD: N/A.

VariantEvidence: N/A.

CaseAddInfo: N/A.

CasePMIDs: N/A.

Case#: 14-year old female index patient, F, Age of Report:, Ethnicity: Austrian.

CasePresentingHPOs: HP:0001252 (Hypotonia), HP:0001945 (Fever), HP:0025297 (Prolonged), HP:0001873 (Thrombocytopenia), HP:0002155 (Hypertriglyceridemia), HP:0025435 (Increased circulating lactate dehydrogenase concentration/increased lactate dehydrogenase), HP:0003281 (Increased circulating ferritin concentration/markedly elevated ferritin), HP:0012156 (Hemophagocytosis),

CaseHPOFreeText: Here we investigated a 14-year old female index patient, born to non-consanguineous healthy Austrian parents, who was hospitalized with severe hypotonia and prolonged fever. She had neither lymphadenopathy nor hepatosplenomegaly, and no infectious agent was found. Initial laboratory findings showed a mild thrombocytopenia, hypertriglyceridemia, increased lactate dehydrogenase (LDH) and markedly elevated ferritin (Table 1 and Figure 1A), prompting work up for hemophagocytic lymphohistiocytosis (HLH). Hemophagocytosis was indeed visible in the bone marrow aspirate (Figure 1B). Soluble CD25 was mildly elevated at 2204 U mL-1 (Table 1) but below the levels typically seen in HLH.6 NK-cell activity as measured by CD107a expression upon stimulation was in the low normal range in the initial diagnostic (Table 1). The presence of fever, hypertriglyceridemia, hyperferritinemia and hemophagocytosis, did not allow the diagnosis of HLH, but gave evidence of macrophage activation in the context of a hyperferritinemic inflammatory syndrome (Table 1).6We initiated treatment with dexamethasone, leading to clinical improvement and normalization of LDH and ferritin levels. Tapering of dexamethasone resulted in clinical deterioration and rise in ferritin (Figure 1A), and was accompanied by the development of autoimmune neutropenia as documented by HNA-1b antibodies. As the disease was distinct from classical HLH,6 we decided to treat the patient with recombinant human anti-IL-1β (Anakinra, 100 mg twice daily) in combination with dexamethasone, rather than using the etoposide-based HLH-94 protocol. We discontinued dexamethasone treatment after eight weeks and, one month later, reduced the Anakinra dose to a maintenance dose of 100 mg daily. The patient has remained clinically stable and is currently receiving Anakinra (decreased to 60 mg once daily) without any inflammatory manifestations. Immunological characterization of patient peripheral blood in the asymptomatic phase after ceasing dexamethasone revealed reduced absolute natural killer (NK)-cell counts and low frequency of monocytes, and slightly low absolute lymphocyte counts (Table 1)..

CaseNotHPOs: N/A.

CaseNotHPOFreeText: She had neither lymphadenopathy nor hepatosplenomegaly, and no infectious agent was found.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WES.

Variant: Variant 1: NM_001282426.2:c.145C>A (p.Arg49Ser) . Variant 2: NM_001282426.2:c.3254A>G (p.Asn1085Ser).

ClinVar: Variant 1: 1675220. Variant 2: 1675219.

CAID: Variant 1: CA4429087. Variant 2: CA368817268.

gnomAD: Variant 1: Frequency: 0.001519. Link: https://gnomad.broadinstitute.org/variant/chr7-106867706-C-A?dataset=gnomad_r4. Variant 2: N/A.

VariantEvidence: N/A.

CaseAddInfo: N/A.

CasePMIDs: N/A.

Case#: A.1, F, Age of Report: 9 y.o., Ethnicity: European-American.

CasePresentingHPOs: HP:0012378 (Fatigue), HP:0001878 (Hemolytic anemia), HP:0006510 (Chronic pulmonary obstruction/early obstructive pulmonary impairment), HP:0003651 (Foam cells), HP:0004313 (Decreased circulating antibody concentration/Hypogammaglobulinemia), HP:0001873 (Thrombocytopenia), HP:0001888 (Lymphopenia), HP:0001880 (Eosinophilia), HP:0100721 (Mediastinal lymphadenopathy), HP:0034388 (Hilar lymph node enlargement), HP:0001744 (Splenomegaly), HP:0004387 (Enterocolitis), HP:0002014 (Diarrhea), HP:0002027 (Abdominal pain), HP:0002583 (Colitis), HP:0005425 (Recurrent sinopulmonary infections), HP:0410018 (Recurrent ear infections), HP:0001581 (Recurrent skin infections), HP:0000010 (Recurrent urinary tract infections), HP:0001742 (Nasal congestion), HP:0011010 (Chronic), HP:0000964 (Eczematoid dermatitis/Eczema),

CaseHPOFreeText: A female patient (hereafter called A.1) from a European-American family presented at nine years of age with fatigue and hemolytic anemia followed by early obstructive pulmonary impairment. A subsequent chest CT scan revealed bilateral nodular infiltrates and areas of patchy, peripheral-basal consolidation in lungs, and histological examination revealed a pattern of interstitial CD3+ lymphocytic infiltration, foamy histiocytes, scattered noncaseating granulomas, and luminal obstruction initially characterized as cryptogenic organizing pneumonia (Fig. 1a–b). Further follow up and analysis revealed clinical progression to hypogammaglobulinemia, thrombocytopenia, various lymphopenias, eosinophilia, mediastinal and hilar lymphadenopathy, and splenomegaly (Table 1). More recently, at sixteen years of age, patient A.1 developed enterocolitis with diarrhea and abdominal pain. Histological assessment of gut tissue revealed interstitial infiltrate of more than 25 CD3+ lymphocytes per 100 epithelial cells (Fig. 1b, bottom). Episodes of pneumonitis and colitis continue to recur intermittently, have an apparent noninfectious etiology (with separate incidences of infectious colitis), and respond to pulse doses of corticosteroids and steroid-sparing measures including mycophenolate mofetil.

The childhood of patient A.1 was remarkable for recurrent sinopulmonary, ear, skin, and urinary tract infections (commonly with S. aureus), chronic nasal congestion, and eczema. Additional episodes of colitis were sometimes associated with stool cultures positive for C. difficile and Salmonella. Vaccination responses were protective for tetanus, borderline protective for diphtheria, and protective for 4 of 23 pneumococcal strains. Warm autoimmune hemolytic anemia at nine years of age (preceding the initial pneumonitis by several months) was treated with steroids and blood transfusions; a recurrence of autoimmune cytopenias at seventeen years prompted CD20+ B cell depletion with rituximab. Patient A.1 is currently treated with immunoglobulin replacement therapy to restore humoral protection and mycophenolate mofetil to suppress inflammation.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WES and Sanger.

Variant: NM_001282426.2:c.3062G>C (p.Arg1021Pro).

ClinVar: 1675218.

CAID: CA164129242.

gnomAD: Frequency: 0.00002988. Link: https://gnomad.broadinstitute.org/variant/chr7-106905140-G-C?dataset=gnomad_r4.

VariantEvidence: N/A.

CaseAddInfo: Patient A.1 inherited an allele from her healthy mother in whom a single base-pair deletion causes a frameshift beginning at R982 of p110γ, and an allele from her healthy father in whom a missense mutation results in an R1021P amino acid substitution in the kinase domain.

CasePMIDs: N/A.

Case#: 15-year-old female, F, Age of Report: 15 y.o., Ethnicity: From China.

CasePresentingHPOs: HP:0001511 (Intrauterine growth retardation/Intrauterine growth restriction), HP:0004322 (Short stature), HP:0000684 (Delayed eruption of teeth/teething delay), HP:0000858 (Irregular menstruation/irregular menstrual cycle), HP:0001007 (Hirsutism), HP:0000820 (Abnormality of the thyroid gland/thyroid disease), HP:0005328 (Progeroid facial appearance/Progeroid facial appearance), HP:0000545 (Myopia), HP:0000678 (Dental crowding/overcrowded teeth), HP:0000855 (Insulin resistance)

CaseHPOFreeText: Proband was noted to have "characteristic facial gestalts/"characteristic facial dysmorphim", low weight at birth,

The proband was admitted to our department due to irregular menstrual cycle and hirsutism with short stature, who had a history of intrauterine growth restriction and presented with short stature, teething delay, characteristic facial gestalts, hirsutism, and thyroid disease. Whole-exome sequencing and Sanger sequencing revealed c.1960C > T, a novel de novo nonsense mutation, leading to the termination of protein translation (p. Gln654*).

This is the first case report of SHORT syndrome complicated with thyroid disease in China, identifying a novel de novo heterozygous nonsense mutation in PIK3R1 gene (p. Gln654*).

The phenotypes are mildly different from other cases previously described in the literature, in which our patient presents with lipoatrophy, facial feature, and first reported thyroid disease. Thyroid disease may be a new clinical symptom of patients with SHORT syndrome.

The patient was a girl born to a physically healthy and non-consanguineous couple by spontaneous delivery at the 37th week. Birth weight was 2150 g (− 3.39SD) and birth length was 44 cm (− 3.41SD), indicating that the patient had intrauterine growth restriction (IUGR). The proband also had teething delay, getting the first tooth at 1 year old. During childhood, the patient was bothered by short stature. Psychomotor and speech development was normal. The height of proband’s father and mother was 168 cm and 155 cm respectively. The patient also had a healthy 20-month-old brother.

At the age of 15 years and 4 months, the proband was referred to our department due to irregular menstrual cycle and hirsutism with a height of 149 cm (− 2.04SD), weight of 43 kg (− 1.22SD) and body mass index (BMI) of 19.4 kg/m2. The height of the proband had remained 149 cm, ever since 13 years old. Physical examination showed a triangular-shaped face, small chin, large low-set ears, thin lip, downturned mouth, obvious beard and bushy eyebrows (Fig. 1a,b,c,d). Oral examination showed overcrowded and irregular teeth, hypodontia, and severe dental caries (Fig. 1g). Pubertal development was assessed according to the Tanner stage, with pubic hair at PH5 stage and breast at B2 stage. The second phalanx of little finger in the left hand was short and thicken, which was confirmed with X-ray (Fig. 1e,f). Ultrasound of neck showed diffuse thyroid disease. Ultrasound biomicroscopy of the eyes, examination of ocular fundus, abdominal ultrasound, reproductive system ultrasound, and chest X-ray were normal. The cranial magnetic resonance imaging (MRI) indicated a small posterior pituitary.

Not evaluated on the proband: OFC at birth, thin, wrinkled skin with readily visible veins, inguinal hernia,

CaseNotHPOs: N/A.

CaseNotHPOFreeText: Proband was noted to not have: Hyperextensibility of joints, ocular depression, Riegar anomaly, lipoatrophy, glaucoma, hyperopia, astigmatism, delayed bone age, intellectual deficiency, speech delay, diabetes, hearing loss, frequent infections, congenital heart diseases, pulmonary stenosis and ovarian cysts.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: Whole-exome sequencing and Sanger sequencing.

Variant: NM_181523.3:c.1960C>T (p.Gln654Ter).

ClinVar: N/A.

CAID: CA359884699.

gnomAD: N/A.

VariantEvidence: A novel de novo heterozygous nonsense mutation in the PIK3R1 gene (p. Gln654*) was found in the proband.

WES was performed to make a clear clinical diagnose. The candidate variants were first screened by a minor allele frequency < 3% against the 1000 Genomes Project, the NHLBI exome variant server or in 50 HapMap control exomes. Then, short stature, facial abnormalities were selected as the filtering clinical symptoms to analyze the screened candidate variants. According to the guidelines recommended by the American College of Medical Genetics and Genomics, a pathogenic variant of PIK3R1 gene was identified to contribute to the patient’s conditions. Sequencing result indicated c.1960C > T of PIK3R1 gene a novel nonsense mutation, leading to the termination of protein translation (p. Gln654*), which was confirmed by sanger sequencing (Fig. 2). In addition, direct sequencing results showed the genotypes of proband’s parents were wild-type, suggesting it was a de novo mutation.

CaseAddInfo: The height of proband’s father and mother was 168 cm and 155 cm respectively. The patient also had a healthy 20-month-old brother.

CasePMIDs: N/A.

Case#: patient, M, Age of Report: newborn, Ethnicity: Korean.

CasePresentingHPOs: HP:0004322 (Short stature), HP:0004325 (Decreased body weight), HP:0040195 (Decreased head circumference), HP:0003074 (Hyperglycemia), HP:0000325 (Triangular face/Facial dysmorphim Triangular shape), HP:0011220 (Prominent forehead), HP:0000490 (Deeply set eye/Ocular depression), HP:0009125 (Lipodystrophy), HP:0000023 (Inguinal hernia), HP:0001642 (Pulmonic stenosis), HP:0001684 (Secundum atrial septal defect/ASD secundum), HP:0000684 (Delayed eruption of teeth)

CaseHPOFreeText: To the best of our knowledge, this is the first case report of SHORT syndrome with TNDM.

The patient was a newborn male and the only child of a healthy non-consanguineous Korean couple with a non-contributory family history. The height of his father and mother was 170 cm (−0.70 SD score) and 160 cm (−0.04 SD score), respectively. They had no dysmorphic features. The mother had regular antenatal check-up and did not have any history of medical and obstetric problems during pregnancy. He was born at 38 weeks of gestation but displayed features of IUGR during pregnancy. His birth weight was 1.8 kg (<3rd percentile), length 44 cm (<3rd percentile), and head circumference 31 cm (<3rd percentile) according to the Korean reference for birth weight based on gestational age and sex. The initial blood glucose level was 70 mg/dl. The baby was exclusively breastfed starting on day 3 and was in generally good condition. However, blood glucose level was between 218 and 263 mg/dl at 5 day of age. At the age of 20 day, his blood glucose level was still high (205–260 mg/dl), and the infant was referred to the endocrine clinic for persistent hyperglycemia assessment. On physical examination, several dysmorphic features (triangular-shaped face, prominent forehead, ocular depression, lipodystrophy at the lumbar region) and inguinal hernia were present. The systolic and diastolic blood pressure measurements were 74 and 42 mmHg, respectively. The serum c-peptide and insulin levels were 2.83 ng/ml (normal: 1.0–3.5) and 120 μU/ml (normal: 2.8–13.5), respectively. Baseline chemistry including serum blood urea nitrogen was 15.3 mg/dl (normal: 7.0–20.0), creatinine 0.9 mg/dl (normal: 0.6–1.2), aspartate aminotransferase 38 U/L (normal: 14–40), and alanine aminotransferase 16 U/L (normal: 9–45), as well as complete blood count profile were within normal range. Urinalysis showed no glucose or ketones. There was no sign of ketoacidosis and the patient had no type 1 diabetes autoantibodies (antibodies against glutamic acid decarboxylase, islet cell, islet antigen-2, and insulin). The liver and pancreas ultrasonography revealed no structural abnormality. Echocardiography at the age of 1 month confirmed mild pulmonary stenosis and ASD secundum (2 mm) which did not require surgical intervention. Neonatal diabetes mellitus (NDM) was suspected on the basis of hyperglycemia occurring within the first month of life that lasted for >2 weeks and required insulin therapy. At age of 25 day, clinical exome sequencing was performed to identify the genetic cause of NDM.

To monitor the glycemic level, his blood glucose was measured at the beginning of each feeding session. The patient was treated with subcutaneous insulin, and blood glucose level gradually stabilized. The blood glucose levels ranged from 110–250 mg/dl during the next 10 days. An adequate glucose level was achieved at 6 weeks of age without insulin treatment. His body weight was 4.4 kg (<3rd percentile) and his length was 61.6 cm (<3rd percentile) at 10 months of age. The patient experienced no hyperglycemic episode and the glycated hemoglobin was 5.0% and insulin level 2.8 μU/ml. At 10 months of age, the patient had no teeth erupted in the oral cavity.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: Urinalysis showed no glucose or ketones. There was no sign of ketoacidosis and the patient had no type 1 diabetes autoantibodies (antibodies against glutamic acid decarboxylase, islet cell, islet antigen-2, and insulin). The liver and pancreas ultrasonography revealed no structural abnormality.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: TruSight One sequencing panel and Sanger sequencing.

Variant: NM_181523.3:c.1945C>T (p.Arg649Trp).

ClinVar: 60763.

CAID: CA344799.

gnomAD: N/A.

VariantEvidence: N/A.

CaseAddInfo: Segregation analysis could not be performed due to the unavailability of parental samples.

CasePMIDs: N/A.

Case#: proband, M, Age of Report: 8 y.o., Ethnicity: British.

CasePresentingHPOs: HP:0008846 (Severe intrauterine growth retardation), HP:0004322 (Short stature), HP:0004325 (Decreased body weight), HP:0040195 (Decreased head circumference), HP:0001510 (Growth delay), HP:0011968 (Feeding difficulties/behavioral feeding difficulties), HP:0001263 (Global developmental delay/psychomotor development delay), HP:0000252 (Microcephaly), HP:0000684 (Delayed eruption of teeth/Dentition), HP:0100543 (Cognitive impairment/delayed intellectual development), HP:0000325 (Triangular face/Facial dysmorphim Triangular shape), HP:0011220 (Prominent forehead), HP:0000582 (Upslanted palpebral fissure/upward-slanting palpebral fissures), HP:0000430 (Underdeveloped nasal alae/thin alae nasi), HP:0100678 (Premature skin wrinkling/Thin, wrinkled skin), HP:0001187 (Hyperextensibility of the finger joints), HP:0010485 (Hyperextensibility at elbow), HP:0009125 (Lipodystrophy)

CaseHPOFreeText:The proband, 8 years of age, is the first child of non-consanguineous Caucasian parents. There are no manifestations of SHORT syndrome in the family. There is no family history of microcephaly or intellectual disability. Following an otherwise uneventful pregnancy, delivery was induced at 38 weeks of gestation on discovery of severe intrauterine growth restriction. His birth weight was 1.97 kg (<0.4th centile, −3.7 SD).

Despite adequate nutritional intake, the patient's growth was significantly delayed. At 12 months of age, his weight was 6.88 kg (<0.4th centile, −3.2 SD), length was 69.5 cm (1st centile, −2.98 SD) and head circumference was 39.5 cm (<0.4th centile, −5.26 SD). Enteral tube feeding was initiated at 9 months of age, which the patient continues to remain dependent on today. Despite extensive investigation of the proband's feeding disorder, no organic cause was identified, and he was diagnosed with behavioral feeding difficulties. Follow-up consultations revealed a persistent development delay and sustained striking microcephaly. Dentition did not start until the age of 2.5 years. At 6 years of age, his weight was 16.2 kg (1st centile, −2.39SD), length was 105.4 cm (1st centile, −2.47 SD) and head circumference was 43.8 cm (<0.4th centile, −6.16 SD). Skeletal survey and extensive endocrine investigation did not find any abnormalities. The patient has not been formally diagnosed with diabetes and is awaiting an oral glucose tolerance test.

Intellectual and psychomotor development is moderate to severely delayed. The patient first walked at 20 months, first smiled at 3 months and spoke his first words aged 3 years. At his current age of 8 years, he attends a special needs school and requires substantial multidisciplinary support. Magnetic resonance imaging of the brain and electroencephalogram performed at 12 months of age was normal. Neurometabolic investigation was also normal. Recurrent ophthalmology investigations revealed a myopic left eye and hypermetropic right eye at 4 years of age. No anterior chamber defects were noted and his ocular pressure was reported as normal. His hearing was formally assessed and reported as normal.

Facial dysmorphic features are subtle but present (see Figure 2): triangular face, prominent forehead, broad eyebrows, slight upward-slanting palpebral fissures, and hypoplastic alae nasi leading to an impression of low columnella nasi. The patient has thin, wrinkled skin with visible veins, most prominently seen on his chest wall. He has hyperextensibility in his finger and elbow joints. Of note, local lipodystrophy of his proximal finger phalanges is also observed.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: Skeletal survey and extensive endocrine investigation did not find any abnormalities. The patient has not been formally diagnosed with diabetes and is awaiting an oral glucose tolerance test.

No anterior chamber defects were noted and his ocular pressure was reported as normal.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: Chromosome breakage studies, Angelman methylation studies and a 60 gene developmental delay and epilepsy panel were normal. Comparative genomic hybridization microarray identified a likely benign maternally inherited Xp11.4 duplication (GRch X:38646145-38687854). Trio-exome sequencing revealed a de novo heterozygous missense variant, c.1456G>A (p.Ala486Thr) in PIK3R1 (NM_181523.3).

Variant: NM_181523.3:c.1456G>A (p.Ala486Thr).

ClinVar: N/A.

CAID: CA359881414.

gnomAD: N/A.

VariantEvidence: N/A.

CaseAddInfo:N/A.

CasePMIDs: N/A.

Case#: 17-year-old female, F, Age of Report:17 y.o., Ethnicity: Cuban descent.

CasePresentingHPOs: HP:0001510 (Growth delay), HP:0004322 (Short stature), HP:0000696 (Delayed eruption of permanent teeth/secondary tooth eruption delay), HP:0000858 (Irregular menstruation/irregular menses), HP:0100607 (Dysmenorrhea), HP:0012384 (Rhinitis), HP:0002099 (Asthma), HP:0001025 (Urticaria), HP:0031796 (Recurrent), HP:0000403 (Recurrent otitis media), HP:0010606 (Hordeolum/hordeolums), HP:0031796 (Recurrent), HP:0012204 (Recurrent vulvovaginal candidiasis/vaginal candidiasis), HP:0032168 (Clostridium difficile colitis), HP:0004315 (Decreased circulating IgG concentration/low IgG levels), HP:0045082 (Decreased body mass index/low BMI), HP:0001382 (Joint hypermobility/hyperextensible joints), HP:0011220 (Prominent forehead), HP:0000325 (Triangular face/Facial dysmorphim Triangular shape), HP:0009765 (Low hanging columella), HP:0000219 (Thin upper lip vermilion/thin upper lip), HP:0007495 (Prematurely aged appearance/aged appearance), HP:0010976 (B lymphocytopenia/low absolute B cells), HP:0410376 (Increased proportion of naive CD8 T cells/elevated CD8 T cell),

CaseHPOFreeText: This is a 17-year-old female of Cuban descent, born to nonconsanguineous parents at 36 weeks gestational age to an uncomplicated pregnancy. Her birth weight and length were average for gestational age (7 pounds, 18 in.). She presented with a history of growth delay, short stature, and secondary tooth eruption delay. She measured below her growth curve at 1 year of age. She had growth hormone testing which resulted normal; however, she received growth hormone therapy from 3 to 10 years of age with a good response. At that time, she underwent genetic testing for short stature; however, no genetic causes of short stature were found. She has a history of irregular menses and dysmenorrhea with work-up for possible etiologies, including polycystic ovarian syndrome (PCOS), resulting negative. She has met all developmental milestones appropriately and has normal cognition.

She has nonallergic rhinitis, mild intermittent asthma, and acute recurrent urticaria. Her history of infections includes recurrent episodes of otitis media since she was toddler requiring placement of 3 sets of ear tubes and tonsillectomy and adenoidectomy. She has a history of recurrent hordeolums and frequent episodes of vaginal candidiasis attributed to the many courses of antibiotics she has received for her various infections. She had one episode of Clostridium difficile colitis 6 months prior to presentation to our clinic. Prior immunologic evaluation at a different institution at 9 years of age was remarkable for low IgG levels, which ranged from 435 to 511 mg/dL [ref 759–1549 mg/dL]. A skin prick test to aeroallergens resulted negative. She did not receive intravenous immunoglobulin (IVIG) or subcutaneous immunoglobulin therapy at that time.

Her physical exam was relevant for short stature (1 percentile, z = − 2.33), low weight for age (< 1 percentile, z = − 2.69), low BMI (15 percentile), and hyperextensible joints. Her facial features were significant for a prominent forehead, triangular face, low-hanging columella, thin upper lip, and aged appearance. Given concern for immune deficiency, a complete immune evaluation was obtained. Her results revealed hypogammaglobulinemia (IgG of 610 mg/dL [ref 694–1618 mg/dL]), with IgM and IgA within the reference range. The lymphocyte subset panel revealed remarkably low absolute B cells (34 cells/μL [ref 130–800 cells/μL]) and percentage (1% [ref 9–30%]). CD4 T cells were within the reference range, and CD8 T cell counts (1091 cells/μL [ref 240–890 cells/μL]) and percentage (40% [ref 17–36%]) were elevated. She had low CD4:CD8 ratio (0.84 [ref 1.00–2.90]). Follow-up B cell panel corroborated the finding of low absolute B cells (70 cells/μL [ref 100–500 cells/μL]) and revealed increased transitional B cells (6.6% CD19 + CD27-CD21-IgM+ [ref 0.5–2.8%]) and naïve B cells (5.9% CD19 + CD27-CD21-CD38- [ref 0.3–2.3%]). ImmunoCAP IgE to aeroallergens was negative, and total IgE was 2 kU/L [ref < 114 kU/L]. Vaccine boosters to S. pneumoniae, H. influenzae, diphtheria, and tetanus were given. Subsequent titers revealed protective antibodies to S. pneumoniae, H. influenzae, and diphtheria and absent response to tetanus. Her lymphocyte mitogen proliferation showed normal lymphocyte responses to phytohaemagglutinin, concanavalin A, and pokeweed mitogen. Viral testing was not performed. At this time, the decision was made to start amoxicillin prophylaxis and monthly IVIG replacement therapy.

After initiating treatment with IVIG, our patient did not have new episodes of ear or sinus infections. IgG levels have remained within normal limits with monthly IVIG therapy. Given the finding of a PIK3R1 pathogenic variant and its known associations with SHORT syndrome, she was referred to ophthalmology and endocrinology. Of note, she started complaining of frequent headaches, not associated with administration of IVIG. Brain and cervical spine MRI revealed a Chiari I malformation for which she is being evaluated by neurosurgery.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: She did not have protective titers to tetanus, diphtheria, pneumococcus, or influenzae.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: Invitae primary immunodeficiency 207-gene panel was obtained.

Variant: NM_181523.3:c.1425+1G>C (n.336+1G>C).

ClinVar: 156009.

CAID: CA170736.

gnomAD: N/A.

VariantEvidence: Results revealed a heterozygous “pathogenic variant” in PIK3R1 (c.1425 + 1G > C) with an autosomal dominant mode of inheritance in association with APDS2. This variant is a missense point mutation affecting a donor splice site in intron 11, resulting in exclusion of exon 11 (Fig. 1). Her parents are not carriers of this pathogenic variant, indicating this is a de novo mutation.

CaseAddInfo: N/A.

CasePMIDs: N/A.

CTLA4 Alteration and Neurologic Manifestations: A New Family with Large Phenotypic Variability and Literature Review

PMID:40149457 Gene:CTLA4 HGNC:HGNC:2505

PMID: 40420664

GENE: PIK3R1

HGNC: 8979

PMID: 39735640

Gene: PIK3R1

HGNC: 8979

PMID: 41026257 GENE: PIK3CD HGNC: 8979

PMID: 39220156 Gene: CTLA4 HGNC:2505

PMID: 41009791 Gene: CTLA4 HGNC: 2505

PMID: 31045771

Gene: PIK3CD

HGNC: 8977

PMID: 41904601 GENE: CTLA4 HGNC: 2505

PMID: 39689284 Gene: CTLA4 HGNC: 2505

PMID: 34097529

Gene: CTLA4

HGNC: 2505

PMID: 41608053 Gene: CTLA4 HGNC: 2505

OS2

OP2

OVS1

PMID: 37435083

Case#: 1

DiseaseAssertion: stargardt disease originally but didn;t have fishtail flecks

FamilyInfo: both unaffected parents carrying heterozygous MFSD8 variants

CasePresentingHPOs:HP:0001272

CaseHPOFreeText:at 5 years old BCVA was measured at a Snellen equivalent at 0.13 in both eyes, at age 8, BCVA had decreased to 0.07 in both eyes, complete absence of all retinal responses on full‐field flash ERG, No fishtail flecks typical of Stargardt disease were observed

CaseNotHPOs: n/a

CaseNotHPOFreeText:n/a

Genotyping Method: HaloPlex target enrichment kit amplified and sequenced using illumina, then WES

PreviouslyPublished: n/a

Variant: c.3113C>T p.(Ala1038Val)

ClinVar: https://www.ncbi.nlm.nih.gov/clinvar/variation/7894/

SupplementalData: MFSD8 variants identified

Case#: 19 year old woman

DiseaseAssertion: Stargardt disease (STGD)

FamilyInfo: no family history of ocular disease

CasePresentingHPOs:HP:0025158

CaseHPOFreeText:20/25 in the right eye and 20/25-1 in the left eye, small irregular perifoveal lesions of both increased and decreased autofluorescence

CaseNotHPOs:na

CaseNotHPOFreeText:na

Genotyping Method: next gen sequencing

PreviouslyPublished: na

Variant: c.6079C > T, p.(Leu2027Phe) c.4139C > T, p.(Pro1380Leu)

ClinVar: not found not found

CAID: not found not found

SupplementalData: “black shadow” in the right eye after getting hit by a volley ball

PMID:39917552

Gene: ABCA4

HGNC ID: 34

Case#: 43 year old woman II:2

DiseaseAssertion: Stargardt disease (STGD1)

FamilyInfo: none of family had co-existing systemic disorders, father carried variant, probands affected suster did not

CasePresentingHPOs:HP:0000007

CaseHPOFreeText: loss of ellipsoid zone, mascular dystrophy with features of bull's eye maculopathy,

CaseNotHPOs: na

CaseNotHPOFreeText: na

Genotyping Method: sanger sequencing

PreviouslyPublished: n/a

Variant: c.4685 T > C, p.(I1562T)

ClinVar: not found

CAID: not found

SupplementalData: probands affected sister did not carry the ABAA4 variant, indicating ABCA4 was not relevant to mascular dystrophy in family, CRX variant was also found

Case#:case 1 II:4

DiseaseAssertion: Stargardt disease (STGD1)

FamilyInfo: mother has identical phenotype as proband, dad and sister asymptomatic, brother was symptomatic at 8 years old, other brother symptomatic at 15 years old.

CasePresentingHPOs: HP:0000007

CaseHPOFreeText: at age 50, with central visual imparement in right eye, 20/40 right, 20/20 left, linear and branching hyperautofluorescent subretinal deposits and extrafoveal RPE atrophy in both eyes,

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

Genotyping Method:

PreviouslyPublished: n/a

Variant: c.6031_6044delins18M/p.(Ile2003LeufsTer41)

ClinVar: not found

CAID: not found

SupplementalData:

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

PMID: 35182466 Gene: GATA4 HGNC ID: 4173

PMID: 37123967 Gene: GATA4 HGNC: 4173

PMID:36263775 Gene: GATA4 HGNC ID:4173

Case: only patient, female,

Disease Assertion: UCD/OTCD

Family Info:

Case Presenting HPOs: HP:0011463 Childhood onset, hyperammonemia (HP:0001987), oroticaciduria (HP:0003218), low plasma citrulline (HP:0003572), vomiting (HP:0002013),

Case HPO FreeText : episodes of nausea, stomachache and temporary elevated trans- aminase

Case NOT HPOs:

Case NOT HPO Free Text: Sanger sequencing revealed no pathogenic mutation. real-time PCR was conducted on blood DNA from the patient and a male control subject using the Applied Biosystems 7300 real time PCR system (Thermo Fisher Scientific). Several primer pairs were designed for OTC (upstream of exon 1 and intron 6) and RPP30 that was used as an autosomal single copy gene reference to generate amplicons suitable for real-time PCR

Test results plasma ammonia: 220 μg/dl (ref 12~ 60 μg/dl) plasma glutamine:1212 nmol/ml (ref 420–700) plasma citrulline: 18.4 nmol/ml (ref 17–43), urinary orotate: 234.3 μmol/g Cr (ref 4.7 ~ 15.9 μmol/g creatinine) Arg: 32.2 nmol/ml (ref 54–130).

Case Previous Testing:

Supplemental Data: Genetic analysis section,

Notes: No variant mutation detected but was found first documented case of OTCD caused by an exonic duplication (exons 1 to 6) of the OTC gene. Further analysis indicated that it resulted from complex rearrangements.

Treatment: protein-restricted diet and by oral sodium phenylbutyrate and arginine.

Variant: NM_000531.6:-

ClinVarID: -

CAID: -

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Case: patient is named case #2, male

Disease Assertion: UCD/OTCD

Family Info:

Case Presenting HPOs: Hyperammonemia (HP:0001987), oriticaciduria (HP:0003218), low plasma citrulline (HP:0003572), neonatal onset(HP:0003623), Hyperglutaminemia (HP:0003217)

Case HPO FreeText:

Case NOT HPOs:

Case NOT HPO Free Text:

Case Previous Testing: GDNA was isolated from lymphocytes. To examine the small mutations in the coding region of the OTC gene, all 10 exons and their flanking intron regions were amplified using PCR, and the nucleotide sequences of the amplified products were determined. To determine the intron 5 sequence of case 2, PCR was performed using primers OTCex5F and OTCint5R, and primers OTCint5F and OTCex6R (Table 1, Fig. 3). The amplified products were subcloned into the pT7 vector and the inserted DNA was sequenced using an automated DNA sequencer. Allopurinol test

Supplemental Data: TABLE 1, Notes:

Variant: NM_000531.6: c.540+265G>A

ClinVarID: NA

CAID: CA658658977

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Case: Patient Proband SS, Female, Caucasian

DiseaseAssertion: UCD/OTCD

FamilyInfo: De novo inheritance, no family history of disease

CasePresentingHPOs: Hyperammonemia (HP:0001987), oroticaciduria (HP:0003218), Childhood onset (HP:0011463)

CaseHPOFreeText:

CaseNOTHPOs: Positive allopurinol test

CaseNOTHPOFreeText:

CasePreviousTesting: Genomic DNA isolated from peripheral blood leukocytes or cultured skin fibroblasts. Amplification by PCR used. SSCP analysis performed. Sequencing of both free and immobilized single strands carried out by dideoxy chain termination method.

SupplementalData: Table 1: Mutations in the Ornithine Transcarbamylase Gene of 17 Females

Variant: NM_000531.6:c.77+1G>A

ClinVarID: 97313

CAID: CA224773

gnomAD:

Case: Female Patient #1, Female, Japanese

DiseaseAssertion: UCD/OTCD

FamilyInfo: N/A

CasePresentingHPOs: Childhood onset (HP:0011463)

CaseHPOFreeText: Onset at 2 years

CaseNOTHPOs:

CaseNOTHPOFreeText: 16% OTC activity

CasePreviousTesting:

Variant: NM_000531.5:c.67C>T (p.Arg23*)

ClinVarID: 97292

CAID: CA224742

gnomAD:

Case: Patient #38, Female, Chinese

DiseaseAssertion: UCD/OTCD

FamilyInfo: No family history of disease, mutation is inherited

CasePresentingHPOs: Hyperammonemia (HP:0001987), oroticaciduria (HP:0003218), vomiting (HP:0002013), coma (HP:0001259), lethargy (HP:0001254), seizures (HP:0001250), childhood onset (HP:0011463)

CaseHPOFreeText: Elevated plasma ammonia at 190 umol/L (Normal: 9-30 umol/L), Elevated urinary orotate at 202 mmol/mmol creatinine (Normal: 0-1.5 mmol/mmol creatinine)

CaseNOTHPOs:

CaseNOTHPOFreeText: Normal plasma glutamine at 13.5 umol/L (Normal: 6-30 umol/L), Normal plasma citrulline at 15.75 umol/L (Normal: 7-35 umol/L)

CasePreviousTesting: gDNA extracted from peripheral blood leukocytes. PCR all coding exons and exon–intron boundaries of the OTC gene using 9 pairs of synthetic oligonucleotide primers, and the primer sequences and annealing temperature. PCR products were then purified and bidirectionally sequenced. The library was sequenced using Illumina HiSeq4000 and generated 150 bp paired-end reads. Data analysis was performed as previously described [Sun Y, Hu G, Liu H, Zhang X, Huang Z, Yan H, et al. Further delineation of the phenotype of truncating KMT2A mutations: the extended Wiedemann–Steiner syndrome. Am J Med Genet A. 2017;173:510–4.]. Multiplex ligation-dependent probe amplification analysis was performed for samples in which Sanger sequencing or WES failed to detect any disease-causing mutation.

Variant: NM_000531.6:c.67C>T (p.Arg23*)

ClinVarID: 97292

CAID: CA224742

gnomAD:

Case: Patient #4, Female, Caucasian

DiseaseAssertion: UCD/OTCD

FamilyInfo: N/A

CasePresentingHPOs: Hyperammonemia (HP:0001987),

CaseHPOFreeText: Elevated plasma ammonia concentration at 123 uM/L

CaseNOTHPOs:

CaseNOTHPOFreeText: Anxiety, plasma citrulline at 2 uM/L

CasePreviousTesting: N/A

Variant: NM_000531.5:c.67C>T (p.Arg23*)

ClinVarID: 97292

CAID: CA224742

gnomAD:

Case: Patient #16, Male

DiseaseAssertion: UCD/OTCD

FamilyInfo: N/A

CasePresentingHPOs: Neonatal onset (HP:0003623), Hyperammonemia (HP:0001987)

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: N/A

Variant: NM_000531.6: c.77+2dupT

ClinVarID: 567293

CAID: CA891844248

gnomAD:

Case: Patient #50, Male

DiseaseAssertion: UCD/OTCD

FamilyInfo: N/A

CasePresentingHPOs: Neonatal onset (HP:0003623), Hyperammonemia (HP:0001987)

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: N/A

Variant: NM_000531.6: c.174G>A (p.Trp58*)

ClinVarID: 97127

CAID: CA224490

gnomAD:

Case: Patient #85, Male

DiseaseAssertion: UCD/OTCD

FamilyInfo: N/A

CasePresentingHPOs:

CaseHPOFreeText:

CaseNOTHPOs: Late Onset

CaseNOTHPOFreeText: Milder phenotype

CasePreviousTesting: N/A

Variant: NM_000531.6: c.298+1G>T

ClinVarID: 97160

CAID: CA224544

gnomAD:

Case: Patient #32, Female

DiseaseAssertion: UCD/OTCD

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: N/A

Variant: NM_000531.6: c.140dup (p.(Asn47LysfsTer8))

ClinVarID:

CAID:

gnomAD:

Case: Patient #7, Female

DiseaseAssertion: UCD/OTCD

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: N/A

Variant: NM_000531.6: c.29_32del (p.Asn10fs)

ClinVarID: 97157

CAID: CA224540

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Case: Patient #15, Female

DiseaseAssertion: UCD/OTCD

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

Variant: NM_000531.6: c.77+1G>A

ClinVarID: 97313

CAID: CA224773

gnomAD:

Case: patient#5 , female, Italian

Disease Assertion: UCD/OTCD

Family Info:

Case Presenting HPOs: irritability(HP:0000737), lethargy(HP:0001254), vomiting(HP:0002013), Oriticaciduria (HP:0003218), low plasma citrulline (HP:0003572), Elevated circulating alanine aminotransferase concentration(HP:0031964), Elevated circulating aspartate aminotransferase concentration (HP:0031956), childhood onset (HP:0011463)

Case HPO FreeText:

Case NOT HPOs:

Case NOT HPO Free Text:

Case Previous Testing: Total RNA was isolated from peripheral blood lymphocytes or lymphoblastoid cell lines and from frozen liver biopsy as described in Chomczynski and Sacchi (1987). For each patient two cDNA syntheses were performed: 10mg of total RNA with 800-1000 ng of oligo dT or 500ng of specific primer NR, mapping in the 3’UTR of OTC cDNA Identification of genetic lesions by amplification of the OTC mRNA, expressed in the liver tissue and intestine, from a non-specific tissue like PBL or lymphoblastoid cell lines. Some mutations, particularly those affecting splicing sites, may have a different expression in liver and PBL . In females, including manifesting carriers, this method allows the identification of deletions and gene rearrangements with certainty, but mutations, decreasing mRNA stability, are unlikely to be detected because the normal allele will constitute the majority of the RNA available for RT-PCR and will be preferentially amplified.

Supplemental Data: Case report section Notes: Hepatomegaly. This mutation, previously reported (Reish et al., 1993), has been correlated with a lethal disease form in a male patient, therefore the mild phenotype in our patient could be explained by a not completely unfavorable X-lyonization

Variant: NM_000531.6: c.928G>T(p.Glu310*)

ClinVarID: 97361

CAID: CA224838

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Case: 24 yo Laotse patient , female

Disease Assertion: UCD/OTCD

Family Info:

Case Presenting HPOs:Hyperammonemia(HP:0001987), Adult onset (HP:0003581), Elevated circulating alanine aminotransferase concentration(HP:0031964), Elevated circulating aspartate aminotransferase concentration(HP:0031956), oriticaciduria(HP:0003218), Aminoaciduria(HP:0003355, Prolonged prothrombin time(HP:0008151), Cerebral edema(HP:0002181),

Case HPO FreeText:

Case NOT HPOs:

Case NOT HPO Free Text:

Case Previous Testing: " Genomic DNA from the patient was isolated from cultivated fibroblasts. Nine pairs of primers were designed from the published sequence of the OTC gene6,7 to allow amplification of all 10 exons including adjacent intron sequences. Single-strand conformational polymorphism analysis of the polymerase chain reaction–amplified individual exon 8 yielded an unusual migration pattern of exon 9

Supplemental Data: Case report section Notes: Patient had a pregnancy 2 years prior and lost the baby. In this case report, She was a 14weeks pregnant(2nd pregnancy) 24yo . She died during this of severe hyperammonemia 5 days after being administered amino acids through parenteral nutrition. She developed signs of encephalopathy stage 4 with maximal dilated unresponsive pupils, brisk oculocephalic reflex, and severe hyperventilation, requiring mechanical ventilation. MRI revealed revealed diffuse cortical edema with loss of white to gray matter distinction. Increased excretion of Gly, Gln, Ser, Thr, and Lys was found in her urine. Treatment with benzoate was started but didn't save the patient.

Variant: NM_000531.6: c.892_893del(p.Trp298Aspfs*15)

ClinVarID: 97348

CAID: CA224820

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Case: patient #11, female, 35yo, slovenian

Disease Assertion: UCD/OTCD

Family Info: family history of the disease,

Case Presenting HPOs: Adult onset(HP:0003581), hyperammonemia(HP:0001987), protein avoidance (HP:0002038)

Case HPO FreeText:

Case NOT HPOs:

Case NOT HPO Free Text:

Case Previous Testing: Sequencing was performed at a 3rd-party sequencing center using a standardized seq of procedures following PCR-free WGS library preparation protocol Illumina TrueSeq DNA Nano and sequenced on Illumina NovaSeq 6000 platform with a mean autosomal depth greater than 30×. Variants were interpreted by a medical doctor specialized in the NGS sequencing data analysis and those classified as likely pathogenic or pathogenic according to the ACMG/AMP standards and guidelines were considered for reporting, while variants of uncertain clinical significance, were not considered. Likely pathogenic and pathogenic variants were further evaluated by the referring clinical geneticist and were considered and reported if they were classified as both a likely diagnostic finding and if they were compatible with the clinical presentation of referral.

Supplemental Data: Table 4 and section 3.1(Case description) Notes:

Variant: NM_000531.6: c.540+265G>A

ClinVarID: 449382

CAID: CA658658977

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Case: patient #113, Male

Disease Assertion: UCD/OTCD

Family Info:

Case Presenting HPOs: Neonatal onset(HP:0003623), Hyperammonemia HP:0001987

Case HPO FreeText:

Case NOT HPOs:

Case NOT HPO Free Text:

Case Previous Testing: GDNA from blood, cultured skin fibroblasts, liver from patients suspected for otc deficiency was used to amplify all 10 exons and exon/intron boundaries using primers listed in Table 1. The amplified DNA fragments were then screened by single-strand conformational polymorphism (SSCP) and the abnormally migrating DNA fragments were sequenced directly from PCR products (w/o subcloning) to identify the mutation. The amino acid residue substitution created by the mutation is examined using an alignment of 26 OTCase sequences from 23 species.

Supplemental Data: Table 4 Notes:

Variant: NM_000531.6: c.867+1G>A

ClinVarID: 97342

CAID: CA224813

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Case: patient #20, Male

Disease Assertion: UCD/OTCD

Family Info: NA

Case Presenting HPOs: Hyperammonemia (HP:0001987), oriticaciduria (HP:0003218), low plasma citrulline (HP:0003572), neonatal onset (HP:0003623)

Case HPO FreeText:

Case NOT HPOs:

Case NOT HPO Free Text:

Case Previous Testing: Genomic DNA was isolated using PUREGENE blood kit from peripheral leukocytes of patients and related family members with informed consents. Amplification by PCR of all 10 exons of the OTC gene was performed using nine pairs of primers designed to span all exons and their adjacent intronic regions. PCR products were subsequently sequenced using ABI3100 Genetic analyzer with BigDye termination ver.3.0.To analyze the activity of OTC protein expressed in the COS-7, high-pressure liquid chromatographic (HPLC) analysis was performed with a Water system, consisting of a model 510 pump and a UV-visible 420 detector.

Supplemental Data: Table 1 Notes:

Variant: NM_000531.6: c.796_805del(p.Ile265AspfsX20)

ClinVarID: NA

CAID: CA2695233326

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Case: patient #1, female Disease Assertion: UCD/OTCD

Family Info:

Case Presenting HPOs: Hyperammonemia (HP:0001987), Juvenile onset (HP:0003621)

Case HPO FreeText:

Case NOT HPOs:

Case NOT HPO Free Text:

Case Previous Testing: "DNA samples were obtained from either peripheral white blood cells or liver biopsies of probands. Patient 1 total liver RNAs were extracted by the acid-phenol-guanidium method and reverse-transcribed in cDNA by hexanucleotide priming using Superscript 11' (Life Technologies, Cergy-Pantoia, France). First strand cDNA was further PCR-amplified using forward and reverse primers specificons 7 and 9 of the OTC gene, respectively. Sequence comparisons were conducted using the FASTA option of the BISANCE package. Secondary protein conformational changes induced by sequence mutations were predicted using the algorithms of the BISANCE package. Nucleotidic changes potentially altering splice sites were studied using the Senapathy's algorithm from the BISANCE package."

Supplemental Data: TABLE 1, Notes:

Variant: NM_000531.6: c.731_739del(p.Leu244Profs)

ClinVarID: 97307

CAID: CA224765

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Case: patient #273, Male

Disease Assertion: UCD/OTCD

Family Info: NA

Case Presenting HPOs: Neonatal onset (HP:0003623)

Case HPO FreeText:

Case NOT HPOs:

Case NOT HPO Free Text:

Case Previous Testing: NA

Supplemental Data: Supplemental table file Notes:

Variant: NM_000531.6: c.818del (p.Glu273Glyfs*16)

ClinVarID: 97338

CAID: CA224807

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Case: patient MW

Disease Assertion: UCD/OTCD

Family Info: NA

Case Presenting HPOs: NA

Case HPO FreeText:

Case NOT HPOs:

Case NOT HPO Free Text:

Case Previous Testing: NA

Supplemental Data: NA Notes: mutation might cause exon 8 kipping durring splicing.

Variant: NM_000531.6: c.718-2A>G

ClinVarID: 97303

CAID: CA224761

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Case: patient #5, male, German Disease Assertion: UCD/OTCD

Family Info: Family history of the disease, Variant found in mother of the patient

Case Presenting HPOs: infantile onset (HP:0003593), oritic aciduria(HP:0003218), hyperammonemia(HP:0001987), hyperglutaminemia(HP:0003217), low plasma citrulline (HP:0003572)

Case HPO FreeText:

Case NOT HPOs:

Case NOT HPO Free Text:

Case Previous Testing: Liver tissues were used to extract RNA that was later used to synthesize cDNA. The products were compared to healthy controls in order to detect variants. gDNA, in order to determine the size of deletions in patient 3 and 4 , a set of intronic primers presumably flanking the deletions was used and specific primers allowed sequencing of exactly those critical regions(sequencing on paper). To estimate the relevance of the identified intronic variants in terms of their capability to induce splicing, we used a score developed by Shapiro and Senapathy. This splice score offers information about the usage of a certain splice site

Supplemental Data: TABLE 1, Notes: died at 11 months, was given medication and low protein diet and was asymptomatic during that time. Died from sever cerebral edema.

Variant: NM_000531.6: c.1005+1091C>G

ClinVarID: N/A

CAID: CA2695233334

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Case: patient #1, male, turkish

Disease Assertion: UCD/OTCD

Family Info: Family history of the disease, Variant found in mother of the patient

Case Presenting HPOs: infantile onset (HP:0003593), coma(HP:0001259), episodic hyperammonemia(HP:0001951), oriticaciduria(HP:0003218)

Case HPO FreeText:

Case NOT HPOs:

Case NOT HPO Free Text:

Case Previous Testing: Liver tissues were used to extract RNA that was later used to synthesize cDNA. The products were compared to healthy controls in order to detect variants. gDNA, in order to determine the size of deletions in patient 3 and 4 , a set of intronic primers presumably flanking the deletions was used and specific primers allowed sequencing of exactly those critical regions(sequencing on paper). To estimate the relevance of the identified intronic variants in terms of their capability to induce splicing, we used a score developed by Shapiro and Senapathy. This splice score offers information about the usage of a certain splice site

Supplemental Data: TABLE 1, Notes: very mild movement disorder, the diagnosis was prenatal so measures were taken from birth,. 2 biopsies were performed and the revealed respectively a 30% and 50 % decrease on OTC activity.

Variant: NM_000531.6: c.867+1126A>G

ClinVarID: 571311

CAID: CA891843643

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Case: patient #2, male, Saudi Arabian

Disease Assertion: UCD/OTCD

Family Info: Family history of the disease, Variant found in mother of the patient, Brother died of hyperammonemic crisis

Case Presenting HPOs: intellectual disability (HP:0001249), Neonatal onset (HP:0003623), seizure(HP:0001250), episodic hyperammonemia(HP:0001951), intellectual disability (HP:0001249)

Case HPO FreeText: hyperammonemic encephalopathy

Case NOT HPOs:

Case NOT HPO Free Text:

Case Previous Testing: Liver tissues were used to extract RNA that was later used to synthesize cDNA. The products were compared to healthy controls in order to detect variants. gDNA, in order to determine the size of deletions in patient 3 and 4 , a set of intronic primers presumably flanking the deletions was used and specific primers allowed sequencing of exactly those critical regions(sequencing on paper). To estimate the relevance of the identified intronic variants in terms of their capability to induce splicing, we used a score developed by Shapiro and Senapathy. This splice score offers information about the usage of a certain splice site

Supplemental Data: TABLE 1, Patient was severely mentally retarded after the age of 2. Low OTC activity

Variant: NM_000531.6: c.540+265G>A(p.Gln180_Glu181insX4)

ClinVarID: 449382

CAID: CA658658977

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Case: no patient #ID, female Disease Assertion: UCD/OTCD

Family Info: NA

Case Presenting HPOs: NA

Case HPO FreeText:

Case NOT HPOs:

Case NOT HPO Free Text:

Case Previous Testing: NA

Supplemental Data: TABLE 1, Notes: NA

Variant: NM_000531.6: c.665del(p.(Gly222ValfsTer8)

ClinVarID: 97289

CAID: CA224738

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Case: no patient #ID, female Disease Assertion: UCD/OTCD

Family Info: NA

Case Presenting HPOs: NA

Case HPO FreeText:

Case NOT HPOs:

Case NOT HPO Free Text:

Case Previous Testing: NA

Supplemental Data: TABLE 1, Notes: NA

Variant: NM_000531.6: c.663+2T>C

ClinVarID: 97285

CAID: CA224732

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Case: no patient #ID, male Disease Assertion: UCD/OTCD

Family Info: NA

Case Presenting HPOs: NA

Case HPO FreeText:

Case NOT HPOs:

Case NOT HPO Free Text:

Case Previous Testing: NA

Supplemental Data: TABLE 1, Notes: NA

Variant: NM_000531.6: c.663+1G>A

ClinVarID: 97283

CAID: CA224730

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Case: no patient #ID, female Disease Assertion: UCD/OTCD

Family Info: NA

Case Presenting HPOs: NA

Case HPO FreeText:

Case NOT HPOs:

Case NOT HPO Free Text:

Case Previous Testing: NA

Supplemental Data: TABLE 1, Notes: NA

Variant: NM_000531.6: c.77+1G>T

ClinVarID: 97314

CAID: CA224774

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Case: no patient ID#, 36yo donor , female

Disease Assertion: UCD/OTCD

Family Info:

Case Presenting HPOs: adult onset (HP:0003581), oriticaciduria (HP:0003218), irritability (HP:0000737), protein avoidance

Case HPO FreeText: hyperammonemic encephalopathy

Case NOT HPOs:

Case NOT HPO Free Text:

Case Previous Testing: N/A

Supplemental Data: TABLE 1, She is vegeterian. The symptoms of OTCD started showing after the patient donated 60% of liver to her sibling. the information reported in this is the biochemical results during hyperammonemic episode following the transplantation. the patient became irritable and confused, and her level of consciousness deteriorated markedly. After hemodialysis the patient recovered.

Variant: NM_000531.6: c.429T>A(p.Tyr143*)

ClinVarID: 1072591

CAID: CA412723166

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

DOI: 10.48550/arXiv.2304.02112

Resource: (BDSC Cat# 7063,RRID:BDSC_7063)

Curator: @bandrow

SciCrunch record: RRID:BDSC_7063

What is this?

Case: no patient ID#, male

Disease Assertion: UCD/OTCD

Family Info: N/A

Case Presenting HPOs: Neonatal onset (HP:0003623)

Case HPO FreeText:

Case NOT HPOs:

Case NOT HPO Free Text:

Case Previous Testing: GDNA was extracted from blood or liver tissues using salt and ethanol precipitation. multiplex amplification for exons 1, 5 and 9 to screen male patients with large deletions. Band intensities were measured using a molecular dynamics phosphoimager.

Supplemental Data: TABLE 2

Variant: NM_000531.6: c.541-2A>G

ClinVarID: 97243

CAID: CA224675

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Case: no patient ID#, male

Disease Assertion: UCD/OTCD

Family Info:

Case Presenting HPOs: Neonatal onset (HP:0003623)

Case HPO FreeText:

Case NOT HPOs:

Case NOT HPO Free Text:

Case Previous Testing: GDNA was extracted from blood or liver tissues using salt and ethanol precipitation. multiplex amplification for exons 1, 5 and 9 to screen male patients with large deletions. Band intensities were measured using a molecular dynamics phosphoimager.

Supplemental Data: TABLE 2,

Variant: NM_000531.6: c.437C>G(p.Ser146*)

ClinVarID: 97201

CAID: CA224606

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Case: patient #573, male

Disease Assertion: UCD/OTCD

Family Info:

Case Presenting HPOs:hyperammonemia (HP:0001987), Neonatal onset (HP:0003623)

Case HPO FreeText:

Case NOT HPOs:

Case NOT HPO Free Text:

Case Previous Testing: GDNA extracted from blood leukocytes using the proteinase K/phenol extraction procedure on a model 340 A nucleic acid extractor (Applied Biosystems). 5mg samples of DNA were digested with BamHI, MspI, or TaqI restriction endonuclease, electrophoresed through 1 % agarose gels, and transferred to a nylon membrane by standard procedures. The blots were then hybridized with a radiolabeled full-length cDNA probe for human OTC.

Supplemental Data: TABLE 3,

Variant: NM_000531.6: c.67C>T(p.Arg23*)

ClinVarID:97292

CAID: CA224742

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Case: patient SM, male

Disease Assertion: UCD/OTCD

Family Info:

Case Presenting HPOs: Hyperammonemia (HP:0001987), Neonatal onset (HP:0003623)

Case HPO FreeText:

Case NOT HPOs:

Case NOT HPO Free Text:

Case Previous Testing: GDNA extracted from blood leukocytes using the proteinase K/phenol extraction procedure on a model 340 A nucleic acid extractor (Applied Biosystems). 5mg samples of DNA were digested with BamHI, MspI, or TaqI restriction endonuclease, electrophoresed through 1 % agarose gels, and transferred to a nylon membrane by standard procedures. The blots were then hybridized with a radiolabeled full-length cDNA probe for human OTC.

Supplemental Data: TABLE 3,

Variant: NM_000531.6: c.274C>T(p.Arg92*)

ClinVarID:97151

CAID: CA224530

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Case: patient from family 1, male

Disease Assertion: UCD/OTCD

Family Info: Family history of the disease

Case Presenting HPOs: coma(HP:0001259), lethargy(HP:0001254), hyperammonemia (HP:0001987), Neonatal Onset HP:0003623

Case HPO FreeText: Poor feeding, poor spirit

Case NOT HPOs:

Case NOT HPO Free Text:

Case Previous Testing: Genomic DNA was extracted using the QIAamp DNA Blood Midi Kit (Qiagen, Duesseldorf, Germany). Quality control assessment of DNA samples was performed using the NanoDrop 2000 ultra-microvolume nucleic acid and protein spectrophotometer (Thermo, Waltham, MA, USA). The purity of DNA was required to be between 1.8 and 2.0.

Supplemental Data: TABLE 1, admitted to neonatal department because of poor feeding, poor spirit, coma, and lethargy. The maternal grandmother of the proband in this family had given birth to 3 boys and 2 girls. Two boys died within 1 month after birth

Variant: NM_000531.6: c.867+1G>C

ClinVarID:N/A

CAID: CA412723994

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Case: patient #5, female

Disease Assertion: UCD/OTCD

Family Info: N/A

Case Presenting HPOs: Neonatal onset (HP:0003623)

Case HPO FreeText:

Case NOT HPOs:

Case NOT HPO Free Text:

Case Previous Testing: gDNA testing involves PCR amplification of all 10 exons and exon/intron boundaries followed by screening for mutations or sequencing of all fragments, For these patients, confirmation of the diagnosis requires enzymatic assays. No specifications about the test

Supplemental Data: TABLE 1

Variant: NM_000531.6: c.53del (p.His18Profs*20)

ClinVarID: 97239

CAID: CA224671

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Case: patient #85, female

Disease Assertion: UCD/OTCD

Family Info: N/A

Case Presenting HPOs:

Case HPO FreeText:

Case NOT HPOs:

Case NOT HPO Free Text:

Case Previous Testing: gDNA testing involves PCR amplification of all 10 exons and exon/intron boundaries followed by screening for mutations or sequencing of all fragments, For these patients, confirmation of the diagnosis requires enzymatic assays. No specifications about the test

Supplemental Data: TABLE 1

Variant: NM_000531.6: c.449_451del(p.Leu151Trpfs*36)

ClinVarID: N/A

CAID: CA2759533410

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Case: patient #154, male

Disease Assertion: UCD/OTCD

Family Info: N/A

Case Presenting HPOs: Neonatal onset (HP:0003623)

Case HPO FreeText:

Case NOT HPOs:

Case NOT HPO Free Text:

Case Previous Testing: gDNA testing involves PCR amplification of all 10 exons and exon/intron boundaries followed by screening for mutations or sequencing of all fragments, For these patients, confirmation of the diagnosis requires enzymatic assays. No specifications about the test

Supplemental Data: TABLE 1

Variant: NM_000531.6: c.664-1G>A

ClinVarID: 97288

CAID: CA224811

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Case: patient #188, male

Disease Assertion: UCD/OTCD

Family Info: N/A

Case Presenting HPOs: Neonatal onset (HP:0003623)

Case HPO FreeText:

Case NOT HPOs:

Case NOT HPO Free Text:

Case Previous Testing: gDNA testing involves PCR amplification of all 10 exons and exon/intron boundaries followed by screening for mutations or sequencing of all fragments, For these patients, confirmation of the diagnosis requires enzymatic assays. No specifications about the test

Supplemental Data: TABLE 1

Variant: NM_000531.6: c.835C>T(p.Gln279*)

ClinVarID: 97341

CAID: CA224811

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Case: patient #213, male

Disease Assertion: UCD/OTCD

Family Info: N/A

Case Presenting HPOs: Neonatal onset (HP:0003623)

Case HPO FreeText:

Case NOT HPOs:

Case NOT HPO Free Text:

Case Previous Testing: gDNA testing involves PCR amplification of all 10 exons and exon/intron boundaries followed by screening for mutations or sequencing of all fragments, For these patients, confirmation of the diagnosis requires enzymatic assays. No specifications about the test

Supplemental Data: TABLE 1

Variant: NM_000531.6: c.962C>A(p.Ser321*)

ClinVarID: 97373

CAID: CA224859

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Case: patient #220, male

Disease Assertion: UCD/OTCD

Family Info: N/A

Case Presenting HPOs: Neonatal onset (HP:0003623)

Case HPO FreeText:

Case NOT HPOs:

Case NOT HPO Free Text:

Case Previous Testing: gDNA testing involves PCR amplification of all 10 exons and exon/intron boundaries followed by screening for mutations or sequencing of all fragments, For these patients, confirmation of the diagnosis requires enzymatic assays. No specifications about the test

Supplemental Data: Table 1

Variant: NM_000531.6: c.1005+2T>C

ClinVarID: 97090

CAID: CA224431

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Case: patient #335, female

Disease Assertion: UCD/OTCD

Family Info: N/A

Case Presenting HPOs:

Case HPO FreeText:

Case NOT HPOs:

Case NOT HPO Free Text:

Case Previous Testing: No specific functional tests indicated

Supplemental Data: In supplemental data files

Variant: NM_000531.6: c.861_862insAC (p.Met288Thrfs*2)

ClinVarID: N/A

CAID: CA2759522140

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Case: patient #303, female

Disease Assertion: UCD/OTCD

Family Info: N/A

Case Presenting HPOs:

Case HPO FreeText:

Case NOT HPOs:

Case NOT HPO Free Text:

Case Previous Testing: No specific functional tests indicated

Supplemental Data: In supplemental data files

Variant: NM_000531.6: c.766G>T(p.256Gly*)

ClinVarID: 870326

CAID: CA412722685

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Case: patient #212, female

Disease Assertion: UCD/OTCD

Family Info: N/A

Case Presenting HPOs:

Case HPO FreeText:

Case NOT HPOs:

Case NOT HPO Free Text:

Case Previous Testing: No specific functional tests indicated

Supplemental Data: In supplemental data files

Variant: NM_000531.6:c.561delA(p.Gly188Valfs*18)

ClinVarID: N/A

CAID: CA2499307429

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Case: patient #198, male

Disease Assertion: UCD/OTCD

Family Info: N/A

Case Presenting HPOs: Neonatal onset (HP:0003623)

Case HPO FreeText:

Case NOT HPOs:

Case NOT HPO Free Text:

Case Previous Testing: No specific functional tests indicated

Supplemental Data: In supplemental data files

Variant: NM_000531.6:c.538C>T(p.Gln180*)

ClinVarID: N/A

CAID: CA412724187

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Case: patient #16, female, Japanese

Disease Assertion: UCD/OTCD

Family Info: N/A

Case Presenting HPOs:

Case HPO FreeText:

Case NOT HPOs:

Case NOT HPO Free Text:

Case Previous Testing: The severity of missense mutations was assessed using conservation and solvent accessible area of the replaced amino acid, calculated destabilization of mutant proteins and their SIFT and PolyPhen2 scores

Supplemental Data: Kido_et_al_2022_fgene_Data Sheet 2

Variant: NM_000531.6:c.77+1G>T

ClinVarID: 97314

CAID: CA224774

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Case: patient #55, male, Japanese

Disease Assertion: UCD/OTCD

Family Info: N/A

Case Presenting HPOs: Seizure (HP:0001250), Hyperammonemia (HP:0001987), Intellectual disability (HP:0001249)

Case HPO FreeText: abnormal brain MRI and brain waves, acute liver failure, corneal opacity

Case NOT HPOs:

Case NOT HPO Free Text:

Case Previous Testing: The mRNA ref seq were, wherein the “A” nucleotide of the start codon ATG constituted as +1 numbering of the cDNA sequence. Met encoded by the start codon ATG also represented +1 for the amino acid numbering as set forth by the preprotein seq. PolyPhen-2, SIFT, and I-Mutant 3 tools were used for predicting the potential impact of an amino acid alteration in missense mutations on the function of each enzyme.

Supplemental Data: Table 1

Variant: NM_000531.6:c.c.929_931del(p.Glu310Valfs*45)

ClinVarID: 858012

CAID: CA916083888

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Case: patient #56, female, Japanese

Disease Assertion: UCD/OTCD

Family Info: N/A

Case Presenting HPOs: ,Hyperammonemia (HP:0001987)

Case HPO FreeText: N/A

Case NOT HPOs:

Case NOT HPO Free Text:

Case Previous Testing: The mRNA ref seq were, wherein the “A” nucleotide of the start codon ATG constituted as +1 numbering of the cDNA sequence. Met encoded by the start codon ATG also represented +1 for the amino acid numbering as set forth by the preprotein seq. PolyPhen-2, SIFT, and I-Mutant 3 tools were used for predicting the potential impact of an amino acid alteration in missense mutations on the function of each enzyme.

Supplemental Data: Table 1, patient had a liver transplant at 12yo.

Variant: NM_000531.6:c.940G>T(p.Glu314*)

ClinVarID: N/A

CAID: CA412726302

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Case: patient #52, female, Japanese

Disease Assertion: UCD/OTCD

Family Info: N/A

Case Presenting HPOs: ,Hyperammonemia (HP:0001987)

Case HPO FreeText: N/A

Case NOT HPOs:

Case NOT HPO Free Text:

Case Previous Testing: The mRNA ref seq were, wherein the “A” nucleotide of the start codon ATG constituted as +1 numbering of the cDNA sequence. Met encoded by the start codon ATG also represented +1 for the amino acid numbering as set forth by the preprotein seq. PolyPhen-2, SIFT, and I-Mutant 3 tools were used for predicting the potential impact of an amino acid alteration in missense mutations on the function of each enzyme.

Supplemental Data: Table 1

Variant: NM_000531.6:c.894G>A(p.Trp298*)

ClinVarID: N/A

CAID: CA412725724

gnomAD:

Gene Name: OTC (ornithine transcarbamylase)

Case: patient #51, male, Japanese

Disease Assertion: UCD/OTCD

Family Info: N/A

Case Presenting HPOs: neonatal(HP:0003623), intellectual disability (HP:0001249), seizure (HP:0001250),Hyperammonemia (HP:0001987)

Case HPO FreeText: Hypertonus, Autism, Acute liver failure. very high blood ammonia

Case NOT HPOs:

Case NOT HPO Free Text:

Case Previous Testing: The mRNA ref seq were, wherein the “A” nucleotide of the start codon ATG constituted as +1 numbering of the cDNA sequence. Met encoded by the start codon ATG also represented +1 for the amino acid numbering as set forth by the preprotein seq. PolyPhen-2, SIFT, and I-Mutant 3 tools were used for predicting the potential impact of an amino acid alteration in missense mutations on the function of each enzyme.