Pair Deletion In Exon Research Articles

Case report: Interleukin-17 targeted biological therapy in netherton syndrome

Netherton syndrome (NS) is rare and multisystemic congenital skin disorder classically distinguied as a triad of congenital ichthyosiform erythroderma, trichorrhexis invaginata (TI), and an atopic diathesis. Recent advances in pathogenesis have explored the role of IL-23/Th17 pathway in NS. Herein, we present a 17 years old girl harbouring homozygous four base pair deletion in exon 26 of the SPINK5 gene, presented with pruritus, scaling, dry skin and generalized eczematous lesions. She was administered anti IL17A (subcutaneous secukinumab) therapy. The treatment was well tolerated and resulted in a favourable clinical response, reduction of the IL17A gene expression and CD4 + Th17 cell population after 6 months which revealed an abrogation of Th17-skewing during therapy.

Isolated Scalp Hematoma

Background: Congenital fibrinogen disorder is a rare autosomal recessive blood coagulation disorder, where majority of patients present with bleeding, whereas a few may paradoxically develop thrombosis. While many of the affected children have prolonged umbilical cord bleeding during the neonatal period, manifestations may go unnoticed till adolescence. We describe such a child with congenital afibrinogenemia Clinical Description: A 12-year-old boy presented with painless diffuse scalp swelling for 2 weeks without any antecedent history of trauma, hemarthrosis, muscle hematoma, or any skin bleed, except a history of prolonged bleeding post trauma since toddler age. Examination revealed diffuse, boggy, nonpulsatile swelling over the entire scalp, more prominent on the right side, without any focal neurological deficit. A noncontrast computed tomography head showed a scalp hematoma without any intracranial bleeding. Blood investigations revealed extremely elevated prothrombin time (PT) and activated partial thromboplastin time (aPTT) with normal platelet counts and normal platelet morphology on peripheral smear. A detailed coagulation work-up revealed an extremely high thrombin time and an almost undetectable Factor I (fibrinogen) level. Genetic analysis revealed a homozygous single-base pair deletion in exon 5 of the fibrinogen gene of alpha chain, thus confirming the diagnosis of congenital afibrinogenemia. Management: The child was managed with multiple fresh frozen plasma transfusions and serial PT/aPTT monitoring. Once PT and aPTT were normalized, transfusions were discontinued. The child is currently on regular follow-up maintaining a fibrinogen level of more than 0.5 g/L. Genetic counseling was done for the family. Conclusion: Congenital afibrinogenemia may be detected late in adolescence with atypical bleeding manifestations. Awareness of this entity may help the physician to suspect this disease. Early and appropriate investigations can be conducted to identify the condition, so that appropriate management can be initiated.

Increased Nuchal Translucency Without Aneuploidy in a Fetus: Abnormal Postnatal Radiograph and a Novel Mutation.

Increased Nuchal Translucency Without Aneuploidy in a Fetus: Abnormal Postnatal Radiograph and a Novel Mutation.

Pathogenic variants in three families with distal muscle involvement

Three families suspected of distal hereditary motor neuropathy underwent genetic screening with the aim to identify the molecular defect underlying the disease. The description of the identification reflects the shift in molecular diagnostics that was made during the last decades. Our candidate gene approach yielded a known pathogenic variant in BSCL2 (p.Asn88Ser) in one family, and via a CMT-capture, in HSPB1 (p.Arg127Trp), in addition to five other variations in Charcot-Marie-Tooth-related genes in the proband of the second family. In the third family, using whole exome sequencing, followed by linkage-by-location, a three base pair deletion in exon 33 of MYH7 (p.Glu1508del) was found, a reported pathogenic allele albeit for a myopathy. After identification of the causative molecular defect, cardiac examination was performed for patients of the third family and this demonstrated abnormalities in three out of five affected family members. Heterogeneity and expansion of clinical phenotypes beyond known characteristics requires a wider set of genes to be screened. Whole exome/genome analysis with limited prior clinical information may therefore be used to precede a detailed clinical evaluation in cases of large families, preventing screening of a too narrow set of genes, and enabling the identification of novel disease-associated genes. In our cases, the variants had been reported, and co-segregation analysis confirmed the molecular diagnosis.

Canine gastrointestinal stromal tumours treated with surgery and imatinib mesylate: three cases (2018-2020).

Gastrointestinal stromal tumours (GISTs) are described in dogs and are histologically diagnosed with the aid of immunohistochemistry to allow differentiation from leiomyomas/leiomyosarcomas. These tumours express c-kit and in some cases could harbour mutations in KIT coding gene. Dogs with a diagnosis of GIST previously confirmed with histopathology and immunohistochemistry were considered for inclusion. Medical records were reviewed for clinical signs at presentation, results of diagnostic tests, tumour location and treatment. To be included, patients had to undergo staging procedures and treatment with imatinib alone or in combination with surgery. Immunohistochemistry and KIT mutational analysis were performed assessing all included cases. Three cases were included. All cases underwent staging procedures and surgical excision. Tumours were located in the stomach (two cases) or caecum (one case). KIT mutational status was assessed and the presence of a 54-base pair deletion in exon 11 was identified in one case. Following surgery, imatinib was used to treat recurrent, metastatic or residual disease and resulted in complete response and stable disease in the macroscopic setting and no evidence of recurrence in the microscopic setting. Follow-up time was 890, 120 and 352 days, respectively. Surgical and medical treatment resulted in a positive outcome in these cases of canine GIST. Imatinib treatment was well tolerated and resulted in a measurable response and a low spectrum of toxicities. Further studies on the tolerability and efficacy of imatinib in solid tumours and GIST are warranted to define its effectiveness and safety.

Neonatal Sotos Syndrome: A Novel Frameshift Mutation of the NSD1 Gene Associated with Neonatal Encephalopathy Presenting without Overgrowth

AbstractSotos syndrome type I is one of the more common genetic overgrowth disorders. It presents classically with macrocephaly, distinctive facial gestalt, and acromegalic features, along with neonatal complications including hypotonia, feeding difficulties, and hypoglycemia with other minor feature inconstancies. The phenotypical overlap of features of this syndrome, more so in neonatal age, thwarts an easy diagnosis. In this case report, a neonate of a nonconsanguineous marriage to a multigravida mother with insignificant obstetric history, presented primarily with respiratory difficulty, central hypotonia, and hypoglycemia. Sparse hair, tall forehead, pointed chin, and lax skin were accompanied by persistent encephalopathy and refractory myoclonic jerks. However, the quintessential features of pre- and postnatal overgrowth were lacking, making the line of diagnosis difficult. On neuroimaging, atypical diffuse pachygyria was found. Clinical exome sequencing revealed heterozygous single base pair deletion in exon 21 of the NSD1 gene on chromosome 5q35, resulting in an unreported frameshift and premature truncation of the protein 19 amino acids downstream to codon 2065, confirming the genetic diagnosis of autosomal dominant Sotos syndrome 1. The neonate later succumbed to death after withdrawal of ventilatory support.

Phenotypic Characterization of Macrophage and Monocyte Populations in the NLRP3 KO DAHL/SS‐Nlrp3em2Mcwi Rat Model

BackgroundThe NLR family pyrin domain containing 3 (NLRP3) inflammasome is a multimeric protein complex that is activated in response to pathogen and damage associated molecular patterns (PAMPs & DAMPs) to initiate inflammatory responses through IL‐1ß, IL‐18, and pyroptosis. Pharmacological inhibition of NLRP3 attenuates inflammatory responses after myocardial infarction and hypertension in rodents. However, the effect of NLRP3 gene loss on basal macrophage and monocyte populations in rats is unknown. We hypothesized that NLRP3 gene loss would not alter macrophage and monocyte phenotype under basal conditions.MethodsCRISPR‐Cas9 was used to induce a 14 base pair deletion in exon 1 of the NLRP3 gene in the DAHL/SSJrHsdMcwi strain to produce NLRP3 KO DAHL/SS‐Nlrp3em2Mcwi rats. NLRP3 KO male (n=11), NLRP3 KO female (n=10), wild type (WT) male (n=5), and WT female (n=10) were studied at 4‐5 mo. Teklad 7034 low salt (0.12% NaCl) diet was provided ad libitum. Proinflammatory M1 (CD11b+CD68+) and anti‐inflammatory M2 (CD11b+CD206+) macrophages (Mɸs) were quantified in CD45+ cells from left ventricle (LV), peripheral blood monocytes (PBMCs), bone marrow (BMDMs), and splenocytes using density gradient centrifugation and flow cytometry.ResultsSex (p<0.01) and genotype (p<0.01) main effects were observed in several morphological characteristics. NLRP3 KO and male rats exhibited significantly increased rat, kidney and LV weights, and LV/tibial length vs WT and female, respectively. Males also displayed significantly increased spleen length and visceral adipose weight vs females (p<0.01). In LV, the percent of CD11b+CD68+ cells was 28% greater in NLRP3 KO vs WT (n=1‐2/group). In PBMCs, the percent of CD11b+CD206+ cells was 13% greater in WT female vs males and NLRP3 KO (n=2‐4/group), while NLRP3 KO females exhibited ~20% less CD11b+CD68+ in splenocytes (n=1‐4/group). In BMDMs, ~60% were positive for CD11b+CD68+, while ~2% were CD11b+CD206+ across all groups (n=1‐2/group).ConclusionPreliminary data suggest that NLRP3 gene loss on a Dahl salt sensitive background is associated with increased proinflammatory M1 Mɸs in LV concomitant with increased LV mass, independent of sex. We hypothesize that NLRP3 may possess an inflammasome independent role in regulating resident LV macrophages under basal conditions.

Infantile Ascending Hereditary Spastic Paralysis with Extrapyramidal and Extraocular Manifestations Associated with a Novel ALS2 Mutation.

Infantile Ascending Hereditary Spastic Paralysis with Extrapyramidal and Extraocular Manifestations Associated with a Novel ALS2 Mutation.

Whole Genome Sequencing of Diamond Blackfan Anemia Syndrome Patients Detects Mutations That Alter mRNA Splicing

Diamond Blackfan anemia syndrome (DBAS) is a rare, heritable bone marrow failure syndrome characterized by severe macrocytic anemia, congenital anomalies and predisposition to cancer, most often diagnosed during infancy. More than 98% of DBAS patients with a molecular diagnosis have mutations in a gene encoding one of the ~80 ribosomal proteins (RP) leading to haploinsufficiency. A molecular diagnosis in a patient with DBAS is critical for a definitive diagnosis, the identification of compatible related transplant donors, and developing reproductive strategies for families. Targeted sequencing of RP genes, single nucleotide polymorphism comparative genome hybridization (SNP array) to detect >30 kb deletions (Farrar et al. Blood. 2011) and exome sequencing (WES) (Ulrisch et al. Am J Hum Genet. 2018) has identified RP mutations in ~80% of patients, leaving ~20% of patients with DBAS without a molecular diagnosis.Targeted sequencing and WES focus on only coding sequences. We hypothesized that remaining 20% of DBAS mutations were in the non-coding regions of RP genes, such as promoters or introns. To test this hypothesis, we collected DNA with informed consent for whole genome sequencing (WGS) analysis from 14 patients with no molecular diagnosis after targeted sequencing, SNP array or WES. On average, we aligned ~3.2x10 7 paired end reads of 250 base pairs for each patient (~65X coverage). We focused our analysis on the sequences in and around the RP genes. To identify deletions, we used a suite of detection tools: DELLY, GRIDSS, MANTA, and LUMPY. More than 90% of deletions identified by any 2 of these tools were confirmed by PCR.We identified 5 deletions in the introns of RP genes, ranging from 11 to 467 base pairs in length, which we hypothesized disrupted splicing of the nascent RNA transcript. To test this, we created minigenes in which we replaced exon 2 of a gamma globin gene with either the WT or mutant RP exon. All wild type exons spliced normally. A 467 base pair deletion in RPL27 exon 3 was sufficient to prevent the correct splicing of that intron. Examination of the eCLIP data for RNA binding proteins revealed that spliceosome complex proteins (including SF3B1, SF3B4 and EFTUD2) and Dead-box RNA helicases bind in the deleted region. A 28 base pair deletion in exon 3 of RPL6 removes a polypyrimidine tract that is a critical part of the 3' splice junction consensus sequence, which we presume is also deleterious. The other 3 intronic deletions did not disrupt splicing.We also identified 2 causative point mutations. A point mutation 5 bases into intron 1 of the RPS26 gene changes a base in the 5' splice donor consensus sequence, which activated a cryptic splice donor in the 5' untranslated region. This aberrant splice removes the ATG initiation codon causing an untranslatable RNA. In another patient, we identified a mutation in exon 1 of the RPS27 gene, judged to be a benign amino acid change. This mutation disrupted splicing.by activating a cryptic splice donor site in the 5' untranslated region which removes the ATG initiation codon and causes a frame shift.We were referred two patients with possible duplications of the RPL35a gene. To identify duplications, we employed MinION long read single molecule sequencing. We had an average read length of ~ 6-10kb with the longest read being 1.3Mb. Overall coverage was >85X. We used minimap2 to align the reads to the reference human genome and used SNIFFLES to call the variants. One patient was the parent of DBAS-affected patient with no history of anemia. In this patient, we identified a duplication of 400 kb that included the entire RPL35a region along with genes on either side. We conclude that this duplication is not likely to cause DBA. The second patient was diagnosed with DBAS. In this patient, we identified a duplication of 4 kb including exons 1 and 2 of RPL35a We conclude that this duplication disrupts the RPL35a gene and is a likely cause of DBA.Whole genome sequencing of 15 DBAS patients identified 5 likely causative mutations in RP genes, confirming that most genetically undiagnosed cases of DBAS will involve known genes encoding RP. We conclude that the pipeline for obtaining a molecular diagnosis for DBAS from targeted sequencing, SNP array, and exome sequencing to whole genome sequencing. DisclosuresVlachos: Novartis: Membership on an entity's Board of Directors or advisory committees. Lipton: Celgene: Membership on an entity's Board of Directors or advisory committees.

Newborn with Failure to Thrive and Diarrhea.

Newborn with Failure to Thrive and Diarrhea.

Abstract 2267: Alterations in TGFβ signaling in ovarian cancer patients with TGFβ receptor 1 variants

Abstract Transforming growth factor β (TGFβ) signals through the TGFβ Receptor 1 (TGFβR1) and is implicated in many aspects of malignancy. TGFβR1 gene is frequently mutated in ovarian carcinomas (OvCa) (Chen, T., et al, Cancer Research 61, 4679-4682, 2001). Susceptibility to numerous cancers is linked to two germline variants of TGFβR1, a G to A single nucleotide polymorphism in intron 7 (Int 7G24A) and a nine base pair deletion in exon 1 (TGFβR1*6A) although the mechanism(s) for this association is still unclear. Since the canonical pathway for TGFβR1 signaling is via phosphorylation of SMAD, the goal was to determine the association of either or both variants with development of subtypes of OvCa and to measure phosphorylation of pSMAD in the epithelium and stroma of OvCas from women with either or both Int 7G24A and TGFβR1*6A. FFPE tissues from 122 women without a history of cancer, and 59 women with OvCa were obtained from St. Elizabeth Healthcare (N. KY) and from 63 women with OvCa through the Cooperative Human Tissue Network (Birmingham Ala). OvCa patients and non-cancer controls were age matched. St. Elizabeth Healthcare IRB gave permission for this study. Tumors were diagnosed in H&E stained histologic sections by a Board Certified Pathologist (LED) and were classified as either Low Malignant Potential (LMP), Type 1 (clear cell, mucinous and low grade serous and endometrioid) or Type 2 (high grade serous, high grade endometrioid, or carcinosarcoma). Variants were identified in extracted DNA from FFPE tissues using PCR, capillary electrophoresis (CE), RFLP, and SSCP. Histologic sections were stained by IHC using the DAKO LSAB2 kit (Agilent) and anti pSMAD 2 (Millipore AB3849-1). Stain was evaluated as cytoplasmic and nuclear Histoscores (stain Area X Intensity) by two observers (LED, JHC). Data were evaluated by “Gene Code” with Gene 1 wild type for both variants, Gene 2 homozygous or heterozygous for Int 7G24A, Gene 3 homozygous or heterozygous for TGFβR1*6A, and Gene 4 having both variants. Usual chi-tests were used to determine significance of contingency tables, ANOVA with multiple comparison adjusted were used for markers. KM plots and proportional hazards were used in survival tests. The frequency in Gene 1, 2, 3, and 4 was significantly different in controls vs. OvCa patients (p = 0.0010); 57.7% of OvCa patients had a TGFβR1 variant vs. 36.6% of controls. Frequency of TGFβR1 variants in 62 patients with Type 2 OvCa was 62.9%. Patient survival differed significantly between patients with LMP, Type 1, and Type 2 OvCa (p <0.0001). Differences in nuclear expression of pSMAD in both tumor epithelial and stromal cells between OvCa types were highly significant (p < 0.0001, p< 0.0092). pSMAD expression decreased significantly in the nuclei of both epithelial and stromal cells in Type 2 tumors. These data indicate that germline variations in the TGFβR1 gene are associated with high grade ovarian cancers and altered SMAD phosphorylation. Citation Format: Julia H. Carter, James P. Schaeper, Taiping Chen, Diane W. Fritz, Leah Focke, Adrian Guy, James A. Deddens, Larry E. Douglass. Alterations in TGFβ signaling in ovarian cancer patients with TGFβ receptor 1 variants [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2267.

A CD33 frameshift variant is associated with neuromyelitis optica spectrum disorders

BackgroundNeuromyelitis optica spectrum disorder (NMOSD) is a rare neuroimmunology disorder predominantly affecting the East Asia population, the reason for this preference remains unknown. Genetic factors such as polymorphisms in human leukocyte antigen (HLA) and interleukins (IL) genes have been reported. Although the familial occurrence of NMOSD is rare, it supports that genetic factors may play a role. MethodsWhole exome sequencing (WES) study was performed on the affected mother and daughter, as well as the unaffected father in a Taiwanese family with NMOSD. A cohort of 19 sporadic patients with aquaporin 4 antibody (AQP4-Ab) positive NMOSD was also recruited; all fulfilled the 2015 International NMOSD Diagnosis Criteria. Sanger sequencing was performed on exon 4 of the CD33 gene on the sporadic NMOSD cohort. ResultsWES study revealed a 19 base pair deletion in exon 4 of the CD33 gene, resulting in frameshift premature truncating protein, which segregated with the affected status. CD33 was the most likely candidate gene due to its known function in immune regulation. A total of 19 sporadic NMOSD patients were tested using Sanger sequencing, including 3 patients with other concomitant autoimmune disorders. Two additional NMOSD patients were found to have the same CD33 frameshift variant, which accounts for 19.04% of all NMOSD patients, and 15% following correction for the familial cases; compared to 2% in Taiwanese population controls. ConclusionIn this study, we identified a 19 base pair deletion in the CD33 gene may be a potential risk locus for NMOSD, which is predicted to cause loss of function of CD33. The loss of CD33 inhibitory function may affect the regulation of the immune system in NMOSD patients. This finding requires further larger cohorts of NMOSD patients and functional study to corroborate.

Mutations in CERKL and RP1 cause retinitis pigmentosa in Pakistani families

This study was conducted to identify the genetic basis of retinal dystrophies in consanguineous Pakistani families. We recruited two families with retinitis pigmentosa (RP) displaying visual difficulties, including nyctalopia and constricted visual fields. Linkage analysis and Sanger sequencing resulted in the identification of a previously reported nonsense mutation, c.847C > T, in exon 5 of CERKL in one family and a novel four-base pair deletion in exon 4 of RP1, c.delAGAA4218_4221, leading to premature protein termination in the second family. Here, we report two RP-causing mutations extending the genetic heterogeneity of the disease.

Dental phenotype of multiple impacted supernumerary teeth in Wiedemann–Steiner syndrome

Wiedemann–Steiner syndrome (WSS) is a rare autosomal dominant disorder characterized by short stature, intellectual disability, developmental delay, hypertrichosis cubiti, and dysmorphic facial features (thick eyebrows with a lateral flare, long eyelashes, vertically narrow and downslanting palpebral fissures, and wide nasal bridge). Dental findings reported with this syndrome are premature eruption of dentition, malocclusion, hypodontia, cleft palate, and retrognathia. We report a 12-year-old boy with a heterozygous two-base pair deletion in exon 22 of the KMT2A gene, resulting in a frameshift and premature truncation of the protein 17 amino acids downstream to codon 1974. Our patient exhibited multiple impacted supernumerary teeth which have never been reported earlier. This extends the dental phenotypic spectrum of WSS. To the best of our knowledge, this is the first reported case from India.

ENAMEL RENAL SYNDROME: A NOVEL HOMOZYGOUS FAM20A FOUNDER MUTATION IN 5 NEW BRAZILIAN FAMILIES

Objective To investigate mutations in FAM20A of 11 unreported patients with ERS from 5 different Brazilian families. Study Design Clinical examination, imaging, renal ultrasonography, laboratory tests and DNA sequencing were performed in 11 patients with ERS. Results The patients' ages ranged from 6 to 25 years old, and the presence of hypoplastic amelogenesis imperfecta, microdontia, spaced teeth, intrapulpal calcification, impacted posterior teeth with hyperplastic pericoronal follicle, gingival fibromatosis, ectopic calcifications on gingival and pericoronal tissues, and nephrocalcinosis were common findings to all patients. Only 4 patients showed abnormal results in laboratory tests (vitamin D, parathyroid hormone, phosphate, calcium). Intellectual disability and renal cysts were present in 2 patients each. Biallelic loss of function mutations in FAM20A gene, characterized by 1 base pair deletion in exon 11 (c.1447 delG) and resulting in a premature stop codon at p.GLU483 LYSfsX24 were detected in all patients strongly suggesting a founder effect. Conclusions Our results reinforce the distinct orofacial features of ERS, which are the clue for kidney examination and genetic testing. Here we report the largest series of patients with ERS of the same population, and describe, for the first time, a founder mutation for FAM20A gene. FAPEMIG, FAPESP, CAPES.

Analysis of factor V in zebrafish demonstrates minimal levels needed for early hemostasis

AbstractIn humans, coagulation factor V (FV) deficiency is a rare, clinically heterogeneous bleeding disorder, suggesting that genetic modifiers may contribute to disease expressivity. Zebrafish possess many distinct advantages including high fecundity, optical clarity, external development, and homology with the mammalian hemostatic system, features that make it ideal for genetic studies. Our aim was to study the role of FV in zebrafish through targeted mutagenesis and apply the model to the study of human F5 variants. CRISPR-mediated genome editing of the zebrafish f5 locus was performed, generating mutants homozygous for a 49 base pair deletion in exon 4. Thrombus formation secondary to vascular endothelial injury was absent in f5−/− mutant embryos and larvae. Despite this severe hemostatic defect, homozygous mutants survived before succumbing to severe hemorrhage in adulthood. Human F5 variants of uncertain significance from patients with FV deficiency were evaluated, and the causative mutations identified and stratified by their ability to restore thrombus formation in larvae. Analysis of these novel mutations demonstrates variable residual FV function, with minimal activity being required to restore hemostasis in response to laser-induced endothelial injury. This in vivo evaluation may be beneficial for patients whose factor activity levels lack correlation with bleeding symptomatology, although limitations exist. Furthermore, homozygous mutant embryos tolerate what is a severe and lethal defect in mammals, suggesting the possibility of species-specific factors enabling survival, and allowing further study not possible in the mouse. Identification of these factors or other genetic modifiers could lead to novel therapeutic modalities.

Enamel renal syndrome: A novel homozygous FAM20A founder mutation in 5 new Brazilian families

Enamel renal syndrome (ERS) is a rare autosomal recessive disorder not fully characterized. Here we investigated ERS characteristics in 11 patients from 5 Brazilian families through clinical examination, imaging, renal ultrasonography, laboratory tests and DNA sequencing. The patients' age ranged from 6 to 25 years-old, and the presence of hypoplastic amelogenesis imperfecta, microdontia, intra-pulpal calcification, impacted posterior teeth with hyperplastic pericoronal follicles, gingival fibromatosis, ectopic calcifications on gingival and pericoronal tissues, and nephrocalcinosis were common findings to all patients. Only 4 patients showed abnormal laboratory tests (vitamin D, parathyroid hormone, phosphate, calcium). Intellectual disability and renal cysts were present in 2 patients each. Biallelic loss of function mutation in FAM20A gene, characterized by one base pair deletion in exon 11, resulting in a frameshift replacing a glutamine at codon 483 for a lysine and terminating at position 24 [NG_029809.1: c.1447delG; p.(Glu483Lysfs*24)], was detected in all patients, strongly suggesting a founder effect. Our results reinforce the distinct orofacial features of ERS, which are the clue for kidney examination and genetic testing. Early diagnosis is essential to minimize the deleterious effects related to ERS. Here we report the largest series of patients with ERS in a same population, and describe, for the first time, a founder mutation for FAM20A.

Neonatal-Onset Hereditary Coproporphyria: A New Variant of Hereditary Coproporphyria.

Genetic mutation of the coproporphyrinogen oxidase (CPOX) gene causes either hereditary coproporphyria (HCP) or harderoporphyria. HCP, a rare hepatic porphyria, causes acute attacks after puberty and rarely accompanies cutaneous symptoms. In contrast, harderoporphyria is an erythropoietic porphyria that represents photosensitivity and hemolytic anemia from the neonatal period. In patients with harderoporphyria, the p.Lys404Glu mutation is found in the homozygous or compound heterozygous state with another mutation, and a marked increase in harderoporphyrin is observed. This report describes a neonate with symptoms of erythropoietic harderoporphyria (photosensitivity of the skin, hemolytic anemia, and jaundice). However, the pattern of porphyrin metabolites of feces was consistent with that of typical HCP, not of harderoporphyria. We found a heterozygous, novel, four-base pair deletion in exon 7 of the CPOX gene, although other mutations including the p.Lys404Glu mutation in CPOX were not found. By unknown etiology, our patient had accompanying adrenocortical insufficiency and 46, XY disorders of sex development. Based on genetic mutation of the CPOX gene and information from a previous similar case report, we consider that neonatal-onset HCP is a variant of HCP.

A novel null HLA-B allele, B*15:375N, due to a seven base pair deletion within exon 3.

Characterization of a novel HLA-B null allele, B*15:375N, with a seven base pair deletion in exon 3.

Whole exome sequencing identifies a novel frameshift mutation in GPC3 gene in a patient with overgrowth syndrome

Overgrowth syndromes are a heterogeneous group of diseases characterized by focal or generalized overgrowth. Many of the syndromes have overlapping clinical features and it is difficult to diagnose the condition based on clinical features alone. In the present study we report on a patient with overgrowth syndrome where extensive investigation did not reveal the cause of disease. Finally exome sequencing revealed a novel hemizygous single base pair deletion in exon 8 of GPC3 gene (chrX:132670203delA) resulting in a frameshift and creating a new stop codon at 62 amino acids downstream to codon 564 (c.1692delT; p.Leu565SerfsTer63) of the protein. The mutation was confirmed by Sanger sequencing. The mother was found to be heterozygous for the mutation. This variation is not reported in the 1000 Genomes, Exome Variant Server (EVS), Exome Aggregation Consortium (ExAC) and dbSNP databases and the region is conserved across primates. Exome sequencing was helpful in establishing diagnosis of Simpson–Golabi–Behmel syndrome type 1 (SGBS1) in a patient with unknown overgrowth syndrome.