Autosomal Dominant Research Articles

A novel de novo nonsense mutation in SALL4 causing duane radial ray syndrome: a case report and expanding the phenotypic spectrum

BackgroundSALL4, a member of the SALL genes family, encodes a zinc-finger transcriptional factor that either activates or represses gene transcription depending on cell type during embryonic development. SALL4 mutations cause extremely variable conditions including Duane-radial ray (DRR), Okihiro, Holt-oram, Acro-renal ocular and IVIC syndromes, all with autosomal dominant inheritance pattern. However, all these syndromes with different terminologies are actually the same entity termed SALL4 related disorders.Case presentationHerein, we examine an Iranian patient suspected to DRR syndrome which has not been previously described in the population. Whole-exome sequencing (WES) was performed to examine pathogenic genes in the proband. Subsequently, Sanger sequencing was used to confirm the mutation found. To elucidate the effects of the identified mutation, clinical data of patient was collected. Morever, the possible impact of the mutation found on the corresponding protein was evaluated using bioinformatics tools. WES identifed a novel de novo heterozygous nonsense mutation in exon 2 of SALL4 gene (c.712 C > T:p.Q238X). Subsequently, segregation and phenotype-genotype correlation analysis as well as in-silico approaches confirmed the autosomal dominance inheritance and disease-causing nature of the identified mutation. In addition, studied patient had features not described previously, including kyphoscoliosis, dimple presacral sinus, barrel chest and artric disc (C6–C7). These manifestations could be additional characteristics of the growing phenotypic spectrum of SALL4 related disorders.ConclusionOur findings could extend the pathogenic mutations and phenotypic spectrum of SALL4 related disorders. Such reports can also aid to conduct genetic counseling, prenatal diagnosis and clinical management for individuals at high risk of SALL4 related disorders.

Fumarate Hydratase Variants and Their Association With Paraganglioma/Pheochromocytoma

ObjectiveTo clarify the link between germline variants in fumarate hydratase (FH), hereditary leiomyomatosis and renal cell cancer (HLRCC), and paraganglioma (PGL) and pheochromocytoma (PCC) we utilize a well-annotated hereditary cancer testing database. MethodsRecords of 120,061 patients receiving germline testing were obtained. FH variants were classified into 4 categories: autosomal dominant (AD) HLRCC variants, autosomal recessive (AR) fumarase deficiency (FMRD), variants, previously reported as PGL/PCC FH variants, and variants of unknown significance (VUS) not previously associated with PGL/PCC (NPP-VUS). Rates of PGL/PCC were compared with those with negative genetic testing. ResultsAbout 1.3% of individuals carried FH variants which were more common among individuals with PGL/PCC compared to those without (3.1% vs 1.3%, P < .0001). PGL/PCC rates were higher among individuals with PGL/PCC FH variants compared to those with negative genetic testing (22.2% vs 0.9%, P < .0001). Neither AD HLRCC variants (0.3% vs 0.9%, P = .35) nor AR FMRD variants (1.4% vs 0.9%, P = .19) carried an increased prevalence of PGL/PCC. An increased prevalence of PGL/PCC was detected in those with NPP-VUS (2.0% vs 0.9%, P = .0023). ConclusionsCertain FH variants confer an increased risk of PGL/PCC, but not necessarily HLRCC. While universal screening for PGL/PCC among all individuals with FH variants does not appear warranted, it should be considered in select high-risk PGL/PCC FH variants.

Demographics and Clinical Characteristics of Autosomal Dominant Spinocerebellar Ataxia in Canada.

Autosomal dominant (AD) spinocerebellar ataxias (SCAs) encompass a large group of rare disorders, which occurs in individuals of different ethnic backgrounds. To date, demographics, and clinical descriptions of AD SCA in Canada are lacking. A retrospective chart review of patients with a genetically confirmed diagnosis of AD SCAs was performed at five tertiary centers across Canada in the provinces of Quebec, Alberta, and Ontario. Demographic, genetic, and clinical information were collected and analyzed. A total of 203 patients with AD SCA were identified. Weighted estimated prevalence of AD SCA in three large Canadian provinces was calculated (2.25 cases per 100.000) which is in keeping with the figures documented worldwide. We found that the distribution of the most common SCA differed when comparing provinces. The most prevalent SCA diagnosis in Ontario was SCA3 (49%), while the most prevalent SCA diagnosis in Alberta and Quebec was SCA2 in26% and 47%, respectively. SCA6 was the third most prevalent SCA subtype in Quebec (14%), which was not seen as commonly in other provinces. SCA1 was uncommonly seen in both Alberta and Quebec, despite being common in Ontario. In this largest Canadian study, we describe the prevalence, distribution, and clinical characteristics of AD SCA. We found that the distribution of the most common SCA differed in the three provinces studied. This finding reflects the heterogenous nature of the Canadian population.

Clinical manifestations of 17 Chinese children with hereditary spherocytosis caused by novel mutations of the ANK1 gene and phenotypic analysis.

Background: Hereditary spherocytosis (HS) is an autosomal dominant (AD) and autosomal recessive (AR) disorder that is mostly caused by mutations of the erythrocyte membrane-related gene ANK1. Methods: Clinical and genetic testing data of 17 HS children with ANK1 gene mutations were retrospectively collected. Clinical manifestations and phenotypic analysis of HS were summarized based on our experience and literature review. Results: A total of 17 mutations of the ANK1 gene were identified from 17 probands (12 sporadic cases and five familial cases), including 15 novel mutations and two previously reported ones. Among the 15 novel variants of ANK1, there were four non-sense mutations, four frameshift mutations, three splicing mutations, three missense mutations and one in-frame deletion of three amino acids. In the present study, HS patients with mutations in membrane binding domains had significantly lower hemoglobin (Hb) levels and higher total bilirubin (T-Bil) levels than those with mutations in regulatory domains. After reviewing and analyzing all available published reports of Chinese HS patients carrying ANK1 mutations in PubMed and Chinese journals, there were no significant differences in Hb, Ret and T-Bil between different mutation types or mutation regions. Conclusion: Mutations of the ANK1 can be inherited or de novo. Clinical manifestations of HS in children caused by ANK1 mutations are similar to those of other types of hemolytic anemia. Our report expands the mutation spectrum of HS, thus providing references for clinical management and genetic counseling of HS.

Long-term prognosis of 35 patients with methionine adenosyltransferase deficiency based on newborn screening in China.

Methionine adenosyltransferase deficiency (MATD) is a rare metabolic disorder caused by mono- or biallelic MAT1A mutations that are not yet well understood. Of the 4,065,644 neonates screened between November 2010 and December 2021, 35 individuals have been diagnosed with an estimated incidence of 1: 116,161 by a cutoff value of methionine 82.7μmol/L and follow-up over 11years. MATD patients with autosomal recessive (AR) type had higher clinical and genetic heterogeneity than those with autosomal dominant (AD) type. Fifteen unrelated AD patients harbored one well-known dominant variant, c.791G>A or c.776C>T, and were clinically unaffected with a mean plasma methionine (Met) value <300μmol/L. Twenty AR cases have unique genotypes and presented a wide range of clinical abnormalities from asymptomatic to white matter lesions. Of them, 10 AR patients displayed severe manifestations, such as verbal difficulty, motor delay, development delay, and white matter lesions, with mean Met >500μmol/L and thereby were treated with a methionine-restricted diet alone or in combination with betaine, folate, or vitamin B6, and were healthy finally. Neurological abnormalities were evidenced in two patients (P16 and P27) with Met values >800μmol/L by MRI scan. Neurological abnormalities were reversed here by liver transplantation or by the determination of S-adenosylmethionine supplementation. Additionally, 38 variants of MAT1A were distributed within patients and carriers, of which 24 were novel and mostly predicted to be damaged. Our findings with an extensive clinical and genetic dataset provided new insights into its diagnosis and treatment and will be helpful for its optimal management in the future.

Distrofias Hereditarias de Retina en España: tres décadas de estudio epidemiológico, clínico y genético

Inherited Retinal Dystrophies (IRDs) are a group of rare diseases with a prevalence of 1:3000-4000 people. They are genetic, primarily affecting retinal photoreceptors and epithelial pigmentary cells, and lead to neurodegeneration and finally apoptosis. In 2021, we published our global results obtained in our registry at the Fundación Jiménez Díaz University Hospital (Madrid, Spain) from 1991 to August 2019. Now, we aimed to update these results until August 2022. Thus, we conducted a retrospective hospital-based cross-sectional study on 4.794 IRD-affected unrelated families from all the Spanish autonomous communities. Families were classified into three phenotypic categories: a) “NON-RP” for cone-dominated phenotypes, b) “RP” (retinitis pigmentosa) for primary rod involvement, and c) “syndromic IRD” when visual plus extra-ocular symptoms are present. Molecular studies included: single-gene studies, clinical exome, whole exome or whole genome sequencing. Overall, 62% (2962/4794) of the families were genetically characterized, in which 1.997 different likely causative variants (5.064 different alleles) were identified in 188 genes. The most common phenotype encountered was RP (59% of families, 2465/4794). Regarding the types of causative alleles, missenses were the most frequent (51%), followed by truncating (nonsense, frameshift, indels and splicing; 44%), while copy number variations were only 2%. The most recurrently mutated genes were PRPH2, ABCA4 and RS1 in autosomal dominant (AD), autosomal recessive (AR) and X-linked (XL) NON-RP families, respectively; RHO, USH2A and RPGR in AD, AR and XL for non-syndromic RP; and MYO7A, USH2A and BBS1 in syndromic IRD. Pathogenic variants ABCA4:p.Arg1129Leu and USH2A:p.Cys759Phe were the most frequent. Our study provides the overall genetic landscape for IRD in Spain, reporting the largest cohort ever presented and a high number of causal genes involved in these diseases. Furthermore, our findings have important implications for genetic diagnosis and counseling, but also for possible therapeutic management

Identification of a Missense Mutation in GJA8 Gene in an Iranian Family with Autosomal Dominant Congenital Cataract.

To identify the causative mutations of autosomal dominant (AD) congenital cataracts in a large Iranian family. The complete and accurate family history and clinical information of participants were collected. A total of 51 family members, including 22 affected and 29 unaffected individuals, were recruited in this study. We performed whole exome sequencing to reveal pathogenic mutation. We used amplification refractory mutation system polymerase chain reaction and Sanger sequencing techniques to confirm segregation in patients and also to rule it out in the healthy participants. A known missense mutation, c.827C>T (S276F), in GJA8 was identified. This mutation was confirmed in all patients. Neither all healthy family members nor 100 healthy individuals who served as controls from general population had this mutation. The missense mutation c. 827C>T in the GJA8 gene is associated with AD congenital lamellar cataract with complete penetrance in a six-generation Iranian family.

A novel heterozygous variant in PANX1 causes primary infertility due to oocyte death.

Variants in the pannexin1 (PANX1) gene have been reported to be associated with oocyte death and recurrent in vitro fertilization failure. In this study, we performed genetic analysis in the patient with female infertility due to oocyte death to identify the disease-causing gene variant in the patient. We characterized one patient from a non-consanguineous family who had suffered from oocyte death and female infertility. Whole-exome sequencing and Sanger sequencing were used to identify the variant in the family. Western blot analysis was used to check the effect of the variant on PANX1 glycosylation pattern in vitro. We identified a novel heterozygous PANX1 variant (NM_015368.4 c.976_978del, (p.Asn326del)) associated with the phenotype of oocyte death in a non-consanguineous family, followed by an autosomal dominant (AD) mode. This variant showed a more delayed emergence of oocyte death than previously reported articles. Western blot analysis confirmed that the deletion variant of PANX1 (c.976_978del) altered the glycosylation pattern in HeLa cells. Our findings expand the variant spectrum of PANX1 genes associated with oocyte death and provide new support for the genetic diagnosis of female infertility.

186. True lock-jaw: a familial update on Fibrodysplasia Ossificans Progressive

Fibrodysplasia ossificans progressiva (FOP) is an extremely rare, disabling condition which is caused by an autosomal dominant allele on chromosome 2q23-24 and the mutation of gene ACVR1. There are only 800 cases worldwide. FOPinduces mineralisation in muscles, tendons, ligaments and connective tissue following minor trauma.

Genetic findings in over 600 individuals with inherited retinal disorders in Finland

AbstractPurpose: To report genetic findings in patients with suspected inherited retinal disorders (IRD) in a large Finnish cohort.Methods: The study was conducted retrospectively on IRD‐patients treated at the Department of Ophthalmology, Helsinki University Hospital between January 1, 2012, and December 31, 2020. Eligibility criteria were met by 786 patients. Clinical diagnosis, genetic testing method and result, relevant family history, and mode of inheritance were drawn from the electronic health registries.Results: Of the 638 patients who underwent genetic testing, 79% received a genetic diagnosis. The genetic findings corresponded to autosomal recessive (AR) inheritance in 242 patients, X‐linked in 158, and autosomal dominant (AD) in 94, whereas pathogenic variants in mitochondrial genes were found in 22 patients. The most common genetic diagnosis was a pathogenic variant in RS1 causing X‐linked retinoschisis (n = 86, 17% of all patients with a positive genetic finding). Of retinitis pigmentosa ‐associated genes, causative variants were most commonly found in CERKL (n = 43, 8.5%), RPGR (n = 31, 6.1%), and EYS (n = 25, 5.0%). CERKL variant c.375C &gt; G, p.(Cys125Trp) and EYS variant c.1155 T &gt; A, p.(Cys385Ter), both with known founder effects in the Finnish population, were frequently discovered (n = 69 and 53, respectively). Variants in the ABCA4 gene explained IRD in 24 patients. Pathogenic variants were also found in CHM (n = 26), OPA1 (n = 16), and CLRN1 (n = 16).Conclusions: The genetic causes of IRDs in Finland differ from other countries because of its isolated population history. Compared to similar studies in other countries, the percentage of patients with a positive genetic finding was higher (79%), which can partly be explained by the enriched founder mutations in the population. About 20% of the patients still lack a genetic diagnosis. These patients might have causative variants that are difficult to detect with current testing methods (such as complex structural variants) or the variants are in genes not yet associated with IRD.

Inborn errors of immunity with loss- and gain-of-function germline mutations in STAT1.

Signal transducer and activator of transcription 1 (STAT1) is a well-known and pivotal molecule in the regulation of the Janus activating kinases (JAK)-STAT pathway, an extensive signalling pathway downstream of several cytokine receptors that plays an indispensable role in immune defence in humans. In the JAK-STAT pathway, STAT1 homodimer-dependent IFN-γ immunity is crucial for defence against intra-macrophagic bacteria, and STAT1/STAT2/IRF9 complex-dependent IFN-α/β immunity is essential for protection against viruses. STAT1 dysfunction causes a wide range of immune dysregulation phenotypes, which have been classified into four disease types, namely, (i) autosomal recessive (AR) complete STAT1 deficiency, (ii) AR partial STAT1 deficiency, (iii) autosomal dominant (AD) STAT1 deficiency, and (iv) AD STAT1 gain-of-function (GOF), based on their mode of inheritance and function. Disease types (i, ii, and iii) are caused by STAT1 loss-of-function (LOF) mutations, whereas disease type (iv) is caused by STAT1 GOF mutations. Notably, rapid and accurate diagnosis of these four diseases can be difficult. In particular, the differential diagnosis of AD STAT1 deficiency and AD STAT1 GOF, which are caused by LOF- and GOF-STAT1 mutations, respectively, can be complicated due to their overlapping clinical symptoms. In addition, more than 150 pathological mutations have been identified in STAT1 across all domains, making functional prediction of novel mutations difficult. Thus, the functional analysis of mutations is necessary for diagnosis. The recently proposed reference database of mutant STAT1 functions based on comprehensive alanine scanning is a useful tool for evaluating unknown STAT1 mutations with high accuracy.

Avascular Necrosis and Minimal Trauma Bone Fractures in Patients with Dyskeratosis Congenita

Introduction: Dyskeratosis congenita (DC) and related telomere biology disorders (TBD) result from germline variants in genes required for telomere maintenance. DC is traditionally characterized by a triad of nail dysplasia, oral leukoplakia, and reticular skin pigmentation. Significant complications include bone marrow failure (BMF), pulmonary fibrosis, liver disease, and hematologic and solid organ malignancies. Previous reports described avascular necrosis (AVN) of the femoral head or humerus in DC/TBD. However, these findings were limited to a few individual case reports. Herein, we present a study of AVN and minimal trauma fractures (MTF) in a large cohort of patients with DC/TBD. Methods: We reviewed medical records of all patients with a confirmed diagnosis of DC/TBD enrolled in the IRB-approved Inherited Bone Marrow Failure Syndromes study (NCT00027274) between 2002 - 2019 for the history of AVN and/or MTF. Data were compiled on DC/TBD characteristics, treatments, as well as body mass index (BMI), lipid profile, bone mineral density (BMD), and 25-hydroxyvitamin D (25[OH]D) levels. We used stratified random sampling to match DC/TBD patients with AVN and/or MTF by age, gender, inheritance pattern and genotype with a control group of DC/TBD patients with no AVN/MTF. Distributional variance was assessed for all t-tests and two-sided p values <0.05 were considered significant. Statistical analysis was carried out using RStudio (Ver 1.4.1106). Results: Forty-two of 233 patients (18%) with DC/TBDs experienced at least one AVN and/or MTF at a median age of 21.9 years (range 4 to 58.7); 15/42 were females (Table 1). Twenty-three patients had AVN alone, 6 had MTF alone, and 13 developed both AVN and MTF (Figure 1). The median age at first AVN was 24.1 years (range 6.3 - 58.7) and at first MTF 13.6 years (range 4 - 44.3). AVN was more common in patients with autosomal recessive/X-linked recessive (AR/XLR)/TINF2 DC (n=20, 21.3%) and developed at a younger age (median 18.8 years, range 6.3 - 47.8) than in patients with autosomal dominant (AD) disease (12.5%; median age 29.9 years, range 11.1 - 58.7); p=0.013. MTF occurred almost exclusively in patients with AR/XLR/TINF2 DC (n=17, 19%) compared with AD DC/TBD (n=1, .9%); p<.0001. There were 68 AVN events in 36 patients (median 2 events/patient, range 1 - 5). The most frequent sites were femoral heads (33/36) followed by humeral heads (5/36) and knees (3/36); 22/33 had bilateral femoral head AVN (Figure 1). Twenty-two of 26 patients with severe BMF received androgen/steroids within 5 years of AVN and 8 received hematopoietic cell transplantation (HCT). Compared with the matched control group, significantly more DC patients with AVN had severe BMF and received androgen/corticosteroids (p<0.02). Importantly, 12/36 DC/TBD patients (33%) developed AVN without prior HCT, corticosteroid, or androgen treatment. 24/36 patients received treatment for AVN, including total hip arthroplasty (n=15) and core decompression (n=5) or other medical intervention (n=4). Median time from diagnosis with AVN to treatment was 0.81 years (range 0.03 - 2.7). We identified 38 MTF events in 19 DC patients; the most frequent fracture site was the femoral diaphysis (11 events in 8 patients) (Figure 1). Fractures occurred spontaneously or during routine activities such as entering a vehicle, running in the playground, or low-impact dancing as per patient reports. Seventeen patients (89%) with MTF had severe BMF, 12 (63%) had received HCT (7 had taken androgens/steroids). Compared with matched controls, significantly more DC patients with MTF had received HCT (p=0.02). Other factors such as BMD, elevated cholesterol, overweight/obesity, and 25[OH]D levels were not significantly associated with AVN or MTF in our cohort. Conclusions: AVN and MTF are highly prevalent in patients with DC/TBDs. AVN developed across the entire DC/TBD spectrum but was significantly associated with severe BMF and AR/XLR/TINF2 DC. MTFs occurred almost exclusively in young patients with severe disease indicated by AR/XLR/TINF2 mode of inheritance. Improved screening and effective clinical management of symptoms for patients at higher risk of developing AVN/MTF is needed. Furthermore, these findings signal the need for future research exploring the mechanism underlying AVN and MTF in patients with DC/TBDs. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Diagnostic Efficacy of Genetic Studies in a Series of Hereditary Cerebellar Ataxias in Eastern Spain.

To determine the diagnostic efficacy of clinical exome-targeted sequencing (CES) and spinocerebellar ataxia 36 (SCA36) screening in a real-life cohort of patients with cerebellar ataxia (CA) from Eastern Spain. A total of 130 unrelated patients with CA, negative for common trinucleotide repeat expansions (SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA12, SCA17, dentatorubral pallidoluysian atrophy [DRPLA], and Friedreich ataxia), were studied with CES. Bioinformatic and genotype-phenotype analyses were performed to assess the pathogenicity of the variants encountered. Copy number variants were analyzed when appropriate. In undiagnosed dominant and sporadic cases, repeat primed PCR was used to screen for the presence of a repeat expansion in the NOP56 gene. CES identified pathogenic or likely pathogenic variants in 50 families (39%), including 23 novel variants. Overall, there was a high genetic heterogeneity, and the most frequent genetic diagnosis was SPG7 (n = 15), followed by SETX (n = 6), CACNA1A (n = 5), POLR3A (n = 4), and SYNE1 (n = 3). In addition, 17 families displayed likely pathogenic/pathogenic variants in 14 different genes: KCND3 (n = 2), KIF1C (n = 2), CYP27A1A (n = 2), AFG3L2 (n = 1), ANO10 (n = 1), CAPN1 (n = 1), CWF19L1 (n = 1), ITPR1 (n = 1), KCNA1 (n = 1), OPA1 (n = 1), PNPLA6 (n = 1), SPG11 (n = 1), SPTBN2 (n = 1), and TPP1 (n = 1). Twenty-two novel variants were characterized. SCA36 was diagnosed in 11 families, all with autosomal dominant (AD) presentation. SCA36 screening increased the total diagnostic rate to 47% (n = 61/130). Ultimately, undiagnosed patients showed delayed age at onset (p < 0.05) and were more frequently sporadic. Our study provides insight into the genetic landscape of CA in Eastern Spain. Although CES was an effective approach to capture genetic heterogeneity, most patients remained undiagnosed. SCA36 was found to be a relatively frequent form and, therefore, should be tested prior to CES in familial AD presentations in particular geographical regions.

ODP117 Pseudohypoparathyroidism Type IB: A Rare Cause of Hypocalcemia

Abstract Introduction Pseudohypoparathyroidism (PHP) describes disorders of hypoparathyroidism that are the result of resistance of target tissues to the actions of parathyroid hormone (PTH). Studies have estimated the prevalence of PHP to be 0.34 in 100,000 in Japan and 1.1 in 100,000 in Denmark. The first biochemical abnormalities to become apparent are elevated serum levels of PTH and elevated serum levels of phosphorus, followed by hypocalcaemia. We present a patient diagnosed with PHP Type 1B (PHP1B), which was presented to us many years after her initial diagnosis, with other major comorbidities now present. Case description This patient is an 81 year old female presenting to the clinic to discuss her previously diagnosed PHP1B. Her past medical history revealed she began having symptoms of intermittent muscle cramping at the age of 22, followed by carpopedal spasms and periorbital paresthesia a year later. She has also had a physical examination significant for a positive Trousseau sign, but no phenotypical signs of Albright hereditary Osteodystrophy (AHO). Lab evidence from 1977 was recovered showing urinary cyclic AMP level &amp;lt;20 nmol/mg after administration of PTH, consistent with PHP1B. The family history in her parents and children has revealed no similar genetic history so far. Other comorbidities she has developed since her diagnosis are hypokalemia, hypothyroidism, osteoporosis with a femur fracture, obesity, chronic kidney disease and nephrolithiasis. She has been continuing treatment throughout her life with calcium, calcitriol and vitamin D supplementation for hypocalcemia. She has been mostly eucalcemic since then, and complains of occasional carpopedal spasms and perioral numbness. Discussion PHP1B is isolated resistance to PTH in the kidney and normal PTH response in bone without features of AHO. PHP1A and 1C have PTH resistance in bone, and both express AHO. These various forms of PHP are due to defects in the GNAS gene that lead to decreased expression of the alpha-subunit of G protein (Gsa). In the absence of molecular analysis, the clinical and biochemical overlap between PHP and related disorders can lead to challenges in diagnostic classification. There are 2 types of PHP1B cases- autosomal dominant (AD) and sporadic. However, the majority of Patients with PHP1B do not have mutations within the GNAS but they have methylation and imprinting defects that result in absence of maternal Gsa. To emphasize, epimutation study rather than sequencing of the coding region in GNAS should be performed for genetic investigation, which has now become standard practice. Although there is no difference in clinical presentation between AD PHP1B and sporadic PHP1B, their differentiation early during the disease onset can help providers give patients more reliable genetic and reproductive counseling and provide optimal medical management of complications such as hypocalcemia. Presentation: No date and time listed

TYPE I HEREDITARY ANGIOEDEMA ASSOCIATED WITH SERPING1 GENE MUTATION

<h3>Introduction</h3> Type I hereditary angioedema (HAE) is characterized by recurrent episodes of swelling of the skin, gastrointestinal tract, and upper airway. Here we present a child with chronic abdominal pain who was found to have a novel deleterious variant in the serine protease inhibitor 1 (<i>SERPING1</i>) gene resulting in autosomal dominant (AD) HAE. <h3>Case Description</h3> The patient is a 9-year-old boy with a history of behavioral changes during febrile illnesses and IgA deficiency who presented with chronic abdominal pain and headaches. He was previously diagnosed with pediatric acute-onset neuropsychiatric syndrome (PANS) at another facility. He had a longstanding history of daily episodes of abdominal pain. He had no personal or family history of angioedema. Laboratory results showed low C4 complement levels (7 mg/dL), which prompted a workup for HAE. Lown C4 was confirmed on multiple occasions and the patient had low C1 esterase inhibitor protein and functional levels. Targeted genetic testing showed a "likely pathogenic" variant in SERPING1 c.1481G>A (p.Arg494Gln). An immune workup showed no abnormality except for partial IgA deficiency with negative anti-IgA antibodies. He was started on prophylactic plasma-derived concentrate of C1 esterase inhibitor with resolution of his symptoms. <h3>Discussion</h3> HAE should be considered in the differential of patients with chronic unexplained abdominal pain even with a negative personal and family history of HAE. The combination of low C4 complement levels, decreased C1 esterase inhibitor levels and excellent response to plasma-derived C1 esterase inhibitors confirm the deleterious effect of the c.1481G>A <i>SERPING1</i> variant and the diagnosis of type I HAE.

Allele-Specific Disruption of a Common STAT3 Autosomal Dominant Allele Is Not Sufficient to Restore Downstream Signaling in Patient-Derived T Cells.

Dominant negative mutations in the STAT3 gene account for autosomal dominant hyper-IgE syndrome (AD-HIES). Patients typically present high IgE serum levels, recurrent infections, and soft tissue abnormalities. While current therapies focus on alleviating the symptoms, hematopoietic stem cell transplantation (HSCT) has recently been proposed as a strategy to treat the immunological defect and stabilize the disease, especially in cases with severe lung infections. However, because of the potentially severe side effects associated with allogeneic HSCT, this has been considered only for a few patients. Autologous HSCT represents a safer alternative but it requires the removal of the dominant negative mutation in the patients’ cells prior to transplantation. Here, we developed allele-specific CRISPR-Cas9 nucleases to selectively disrupt five of the most common STAT3 dominant negative alleles. When tested ex vivo in patient-derived hematopoietic cells, allele-specific disruption frequencies varied in an allele-dependent fashion and reached up to 62% of alleles harboring the V637M mutation without detectable alterations in the healthy STAT3 allele. However, assessment of the gene expression profiles of the STAT3 downstream target genes revealed that, upon activation of those edited patient cells, mono-allelic STAT3 expression (functional haploinsufficiency) is not able to sufficiently restore STAT3-dependent signaling in edited T cells cultured in vitro. Moreover, the stochastic mutagenesis induced by the repair of the nuclease-induced DNA break could further contribute to dominant negative effects. In summary, our results advocate for precise genome editing strategies rather than allele-specific gene disruption to correct the underlying mutations in AD-HIES.

Analysis of RPGR gene mutations in 41 Chinese families affected by X-linked inherited retinal dystrophy.

Background: This study analyzed the phenotypes and genotypes of 41 Chinese families with inherited retinal dystrophy (IRD) and RPGR gene mutations. Methods: This retrospective analysis evaluated a cohort of 41 patients who were subjected to a specific Hereditary Eye Disease Enrichment Panel (HEDEP) analysis. All (likely) pathogenic variants were determined by Sanger sequencing, and co-segregation analyses were performed on the available family members. All cases were subjected to Sanger sequencing for RPGR open reading frame 15 (ORF15) mutations. Results: A total of 41 probands from different families with a clinical diagnosis of retinitis pigmentosa (RP; 34 cases) and cone-rod dystrophy (CORD; 7 cases) were included in this cohort. According to clinical information, 2, 18, and 21 cases were first assigned as autosomal dominant (AD), sporadic, and X-linked (XL) inheritance, respectively. Several cases of affected females who presented with a male phenotype have been described, posing challenges at diagnosis related to the apparent family history of AD. Mutations were located in RPGR exons or introns 1–14 and in ORF15 of 12 of 41 (29.3%) and 29 of 41 (70.7%) subjects, respectively. Thirty-four (likely) pathogenic mutations were identified. Frameshifts were the most frequently observed variants, followed by nonsense, splice, and missense mutations. Herein, a detailed description of four RP patients carrying RPGR intronic mutations is reported, and in vitro splice assays were performed to confirm the pathogenicity of these intronic mutations. Conclusion: Our findings provide useful insights for the genetic and clinical counseling of patients with XL IRD, which will be useful for ongoing and future gene therapy trials.

DISCOVERY OF GERMLINE MOSAICISM, NON-PENETRANT DISEASE, AND MORE FOLLOWING DIAGNOSIS OF AUTOSOMAL DOMINANT DISORDERS IN DONOR-CONCEIVED OFFSPRING

Current counseling recommendations following a diagnosis of an apparently de novo autosomal dominant (AD) disorder in a child cite a recurrence risk of approximately 1% due to the possibility of germline mosaicism [REF; Clarke 8th Edition (Harper) p.32]. When an AD disorder is identified in a donor-conceived offspring, investigation for germline mosaicism in the donor can help clarify reproductive risks for other recipient families. Here we summarize experience from investigations of AD diagnoses in donor-conceived offspring to illustrate why such investigations are warranted.

S2677 A Case of Blue Rubber Bleb Nevus Syndrome in an Elderly Patient

Introduction: Blue Rubber Bleb Nevus Syndrome (BRBNS) is an uncommon disorder with only about 200 cases reported worldwide. It is defined by the formation of soft rubbery venous blebs that mostly involve the skin, gastrointestinal (GI) tract, central nervous system, spleen and other visceral organs. BRBNS is mostly diagnosed in children with only 4% incidence noted in adult age groups. Herein we describe the case of the oldest reported individual newly diagnosed with BRBNS who was a 90 year-old lady presenting with small bowel bleeding. Case Description/Methods: A 90-year-old woman with history of atrial fibrillation on apixaban presented to the emergency room with a few week history of melena. Vital signs were significant for tachycardia with a heart rate of 110 beats/min. Physical exam showed pale conjunctiva with no noted cutaneous lesions. Laboratory tests were significant for a hemoglobin of 7.2 g/dL down from a normal baseline (normal range 12-16 g/dL). Upper endoscopy showed non bleeding submucosal venous structures in the esophagus and duodenum (panel A, B). Colonoscopy showed coffee ground blood with no noted source of bleeding. Capsule endoscopy revealed numerous venous structures in the small bowel with active oozing in the jejunal loops suggestive of BRBNS (panel C). A single-balloon assisted deep enteroscopy was offered to attempt to control the bleeding however the patient preferred to avoid any further endoscopic or surgical interventions and chose to receive palliative care. (Figure) Discussion: Most BRBNS cases are sporadic however inheritance through autosomal dominance fashion via TEK gene mutations have been reported in a minority of cases. GI involvement by BRBNS usually manifests as GI bleeding that can range from a chronic slow rate to a massive and life-threatening hemorrhage. Presentation with bowel volvulus, intussusception, infarction and gangrene have been reported. Direct examination through endoscopic visualization is the diagnostic and potentially therapeutic intervention of choice. Management depends on the initial presenting symptoms and extent of involved areas and include iron supplementation, blood transfusion and endoscopic control of bleeding. Surgical resection of affected bowel loops is reserved for complicated and refractory cases. Ongoing clinical trials evaluating the efficacy and safety of sirolimus, interferon-beta and octreotide are underway for the management of complex cases. Recurrence is common and no curative treatment is currently available.Figure 1.: Panel A: Upper endoscopy showing non-bleeding venous structures in the esophagus. Panel B: Upper endoscopy showing non-bleeding venous structures in the duodenum. Panel C: Capsule endoscopy revealing numerous venous structures in the small bowel.

Identification of variants in genes associated with autoinflammatory disorders in a cohort of patients with psoriatic arthritis

ObjectivesBesides adaptive immunity genes, genetic risk factors for psoriatic arthritis (PsA) include innate immunity loci, which suggests an autoinflammatory disease mechanism, at least in a subset of patients. Here, we...