Heterozygous Mutation In Exon Research Articles

Prevalence of PIK3CA Mutation Based on Tumour Locations Among Colorectal Cancer Patients in Bali

Colorectal tumour location is important in determining therapeutic strategies because the location of the tumour will affect the histological and molecular characteristics of the cancer. Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) is a gene known to be associated with colorectal cancer location. The prevalence of PIK3CA mutations in colorectal cancer (CRC) ranges from 10-20%. Although the prevalence is small, this gene has a potential as a predictive and prognostic biomarker in the management of CRC. 80% of PIK3CA mutations occur in exon 9 (codon 542 and 545) and exon 20 (codon 1047). This study aimed to determine the prevalence of PIK3CA gene mutations based on tumour location among colorectal cancer patients in Bali, especially in Prof. dr. I G.N.G. Ngoerah Hospital, Denpasar, Bali. DNA was isolated from formalin-fixed-paraffin embedded (FFPE) blocks of colorectal cancer samples which were stored in the Department of Pathology of Prof. dr. I G.N.G. Ngoerah Hospital. Mutation was detected using polymerase chain reaction (PCR) and direct sequencing. Data on age, gender, and tumour location were recorded from patient medical records. Our findings on 31 colorectal cancer samples showed 26 samples (96.3%) were found with heterozygous mutation in exon 9 with AC genotype, but no mutation was found on exon 20. Based on tumor location, among 26 samples with mutation, 16 samples (61.5%) were left colorectal cancer and 10 samples (38.5%) were right colorectal cancer. Further studies are needed to identify the association of this mutation with colorectal cancer location and the other clinicopathological aspects of CRC. Keywords: Colorectal cancer, PIK3CA gene mutation, PIK3CA exon 9, PIK3CA exon 20, colorectal cancer location, left-sided colorectal cancer, right-sided colorectal cancer

A Family with Congenital Dysfibrinogenemia and Blood Transfusion

To investigate a family with congenital dysfibrinogenemia, and analyze the risk of hemorrhage and thrombosis and blood transfusion strategies. Prothrombin time (PT), activated partial thromboplastin time (APTT) and thrombin time (TT) of the proband and her family members were detected by automatic coagulometer, fibrinogen (Fg) activity and antigen were detected by Clauss method and PT algorithm respectively. Meanwhile, thromboelastometry was analyzed for proband and her family members. Then, peripheral blood samples of the proband and her family members were collected, and all exons of FGA, FGB and FGG and their flanks were amplified by PCR and sequenced to search for gene mutations. The proband had normal APTT and PT, slightly prolonged TT, reduced level of Fg activity (Clauss method). The Fg of the proband's aunt, son and daughter all decreased to varying degrees. The results of thromboelastogram indicated that Fg function of the proband and her family members (except her son) was basically normal. Gene analysis showed that there were 6233 G/A (p.AαArg35His) heterozygous mutations in exon 2 of FGA gene in the proband, her children and aunt. In addition, 2 polymorphic loci were found in the family, they were FGA gene g.9308A/G (p.AαThr331Ala) and FGB gene g.12628G/A (p.BβArg478Iys) polymorphism, respectively. The proband was injected with 10 units of cryoprecipitate 2 hours before delivery to prevent bleeding, and no obvious bleeding occurred during and after delivery. Heterozygous mutation of 6233G/A (p.AαArg35His) of FGA gene is the biogenetic basis of the disease in this family with congenital dysfibrinogenemia.

A case of infantile hypophosphatasia: Phenotypic findings of a compound heterozygous inheritance with a novel mutation

We report the case of a 9-month infant who presented with failure to thrive and bony deformities, mimicking a ricket-like picture. Biochemical parameters showed hypercalcemia, low serum alkaline phosphatase, normal serum phosphorus, magnesium, and parathormone levels. Ultrasound revealed nephrocalcinosis. Clinical exome sequencing revealed infantile hypophophatasia with two compound heterozygous mutations in exon 6 (mutation being novel) and 12. To the best of our knowledge, compound heterozygous mutations in exon 9 and exon 12 have presented with pyridoxine responsive seizure (PRS) along with hypophosphatasia (HPP). This is the third case of infantile HPP reported from India, but with a novel mutation who had not yet manifested with PRS.

A family with type A insulin resistance syndrome caused by a novel insulin receptor mutation.

A 17-year-old boy was referred to our endocrinology clinic for a clinical investigation of hyperinsulinemia. An oral glucose tolerance test showed plasma glucose concentrations in the normal range. However, insulin concentrations were considerably elevated (0 min: 71 μU/mL; 60 min: 953 μU/mL), suggesting severe insulin resistance. An insulin tolerance test confirmed that he had insulin resistance. There was no apparent hormonal or metabolic cause, including obesity. The patient had no outward features of hyperinsulinemia, including acanthosis nigricans or hirsutism. However, his mother and grandfather also had hyperinsulinemia. Genetic testing showed that the patient (proband), his mother, and his grandfather had a novel p.Val1086del heterozygous mutation in exon 17 of the insulin receptor gene (INSR). Although all three family members have the same mutation, their clinical courses have been different. The onset of the mother's diabetes was estimated at 50 years, whereas the grandfather developed diabetes at 77 years. Type A insulin resistance syndrome is caused by mutations in the insulin receptor (INSR) gene and results in severe insulin resistance. Genetic evaluation should be considered in adolescents or young adults with dysglycemia when an atypical phenotype, such as severe insulin resistance, or a relevant family history is observed. Clinical courses may differ even if the same genetic mutation is found in a family.

Novel Calcium-Sensing Receptor (CASR) Mutation in a Family with Autosomal Dominant Hypocalcemia Type 1 (ADH1): Genetic Study over Three Generations and Clinical Characteristics

Introduction: Activating mutation of the calcium-sensing receptor gene (CASR) reduces parathyroid hormone secretion and renal tubular reabsorption of calcium, defined as autosomal dominant hypocalcemia type 1 (ADH1). Patients with ADH1 may present with hypocalcemia-induced seizures. Calcitriol and calcium supplementation in symptomatic patients may exacerbate hypercalciuria, leading to nephrocalcinosis, nephrolithiasis, and compromised renal function. Methods: We report on a family with seven members over three generations with ADH1 due to a novel heterozygous mutation in exon 4 of CASR: c.416T>C. Results: This mutation leads to substitution of isoleucine with threonine in the ligand-binding domain of CASR. HEK293T cells transfected with wild type or mutant cDNAs demonstrated that p.Ile139Thr substitution led to increased sensitivity of the CASR to activation by extracellular calcium relative to the wild-type CASR (EC₅₀ of 0.88 ± 0.02 m<sc>M</sc> vs. 1.1 ± 0.23 m<sc>M</sc>, respectively, p < 0.005). Clinical characteristics included seizures (2 patients), nephrocalcinosis and nephrolithiasis (3 patients), and early lens opacity (2 patients). In 3 of the patients, serum calcium and urinary calcium-to-creatinine ratio levels obtained simultaneously over 49 patient-years were highly correlated. Using the age-specific maximal-normal levels of calcium-to-creatinine ratio in the correlation equation, we obtained age-adjusted serum calcium levels that are high enough to reduce hypocalcemia-induced seizures and low enough to reduce hypercalciuria. Conclusion: We report on a novel CASR mutation in a three-generation kindred. Comprehensive clinical data enabled us to suggest age-specific upper limit of serum calcium levels, considering the association between serum calcium and renal calcium excretion.

A novel STAT1 loss-of-function mutation associated with Mendelian susceptibility to mycobacterial disease.

Mendelian susceptibility to mycobacterial diseases (MSMD) is a rare congenital immune deficiency characterized by susceptibility to weakly virulent mycobacteria. Loss-of-function (LOF) mutation of signal transducer and activator of transcription 1 (STAT1) is one of the common genetic causes of MSMD. In this study, we identified a patient who presented with multiple lymph node enlargements and multiple osteolytic disruptions. Mycobacterium gordonae infection was confirmed by metagenomic next-generation sequencing. Whole-exome sequencing identified a novel paternal heterozygous mutation in exon 22 of STAT1 (NM_007315.4, c.1892T>C, p.Val631Ala). This variant was confirmed pathogenic by multiple software predictions. Based on functional assays, STAT1 expression in STAT1V631A cells was not different from STAT1WT cells. But STAT1V631A mutation caused much lower activation of STAT1 when stimulated by interferon-γ (IFN-γ). Fluorescence localization analysis revealed that both STAT1V631A and STAT1WT proteins were located in the cytoplasm, and only a few STAT1V631A proteins were translocated to the nucleus in response to IFN-γ. These results suggest that STAT1V631A leads to LOF in IFN-γ-mediated mycobacterial immunity, resulting in MSMD. Treatment with antibiotics has achieved ideal disease control for this patient, and no adverse events occurred during follow-up. The STAT1 LOF deficiency is a genetic cause of MSMD, which should be considered in patients with mycobacterial disease, especially those with bone involvement.

P317 Phaeohyphomycosis caused by Phialophora verrucosa in a patient with CARD9 mutations

Poster session 2, September 22, 2022, 12:30 PM - 1:30 PMObjectivesTo study an intractable case of phaeohyphomycosis caused by Phialophora verrucosa and the underlying genetic and immunological mechanisms.MethodsClinical and laboratory findings of the patient were studied. The patient's DNA was sequenced for CARD9. Innate and adaptive immunological responses of patient-derived PBMCs were evaluated with ELISA and flow cytometry.ResultsA 29-year-old Chinese male, born to nonconsanguineous parents, developed an enlarging plaque on his right anterior tibia at 25 years and underwent a 15-month treatment of oral itraconazole at the local hospital. Upon discontinuation of the medication, the plaque spread over his face, upper limbs, and back. Physical examination indicated dark brown verrucous plaques and nodules with surface ulcers and scabs on his right leg, upper limbs, and face. Skin biopsy revealed pigmented yeast cells with budding and yeast cell chain in the dermis. Based on tissue culture, we identified P. verrucosa as the causative pathogen, which was further validated by ITS, BT, and TEF gene sequencing. Thus, subcutaneous phaeohyphomycosis was diagnosed, and itraconazole combined with amphotericin B was prescribed. The lesions improved only marginally. We, therefore, gave him oral posaconazole instead, based on in vitro antifungal susceptibility results. After 1 month of posaconazole treatment, the serum BG assay value decreased and the lesions improved markedly.Based on previous reports linking CARD9 deficiency to phaeohyphomycosis, as well as early onset and recalcitrance characters, Sanger sequencing was performed in this patient and identified two compound heterozygous mutations in exon 6 (R373P) and exon 8 (D274GfsX60) of CARD9. We then evaluated the functional effect of the CARD9 mutations by assessing the stimuli-dependent release of proinflammatory cytokines and helper T cell differentiation. Cytokine production was markedly impaired in PBMCs post 24 h of stimulation with LPS, curdlan, TDB, mannan, MDP, β‐glucan, and various fungal ligands. Moreover, the patient showed a significant absence in Th22 and Th17 cell proportions, as well as lower IL-17A and IL-22 production after six days of co-incubation with the stimuli mentioned above.ConclusionOur report highlighted that otherwise healthy patients diagnosed with early-onset, unexplained, and recalcitrant phaeohyphomycosis should be analyzed for CARD9 mutations and immune deficiency. Furthermore, posaconazole may be an alternative worth trying after the failure of other antifungals due to its ideal results achieved in our case.

Novel compound heterozygous mutations in the desert hedgehog (DHH) gene in cases of siblings with 46,XY disorders of sexual development

BackgroundDisorders of sex development (DSD) are congenital disorders in which the development of the chromosomal, gonadal, or anatomical sex is atypical. Mutations in various genes can impede gonadal development, hormone synthesis, or hormone function and cause DSD.MethodsExome sequencing was performed for two siblings with 46,XY DSD. All mutations identified by exome sequencing were confirmed by Sanger sequencing.ResultsThe 13-month-old younger sibling had a female appearance of the external genital with a clitoris that was assessed as Prader III and scored 2 in the external masculinization score evaluative test. The 16-year-old elder sibling had severe hypospadias. Exome sequencing revealed compound heterozygous mutations in exon 3 of DHH in the siblings with 46,XY DSD. The frameshift mutation (NM_021044.3: c.602delC) was derived from the father and was predicted to be deleterious. The (c.937G > T) substitution mutation was derived from the mother.ConclusionsNovel compound heterozygous mutations of DHH led to 46,XY DSD in two siblings. This study expands the phenotypic mutation spectra of DHH in patients with 46,XY DSD.

Novel de novo missense mutation in the interferon regulatory factor 6 gene in an Italian infant with IRF6-related disorder

BackgroundCongenital maxillomandibular syngnathia is a rare craniofacial anomaly leading to difficulties in feeding, breathing and ability to thrive. The fusion may consist of soft tissue union (synechiae) to hard tissue union. Isolated cases of maxillomandibular fusion are extremely rare, it is most often syndromic in etiology.Case presentationClinical management of a female newborn with oromaxillofacial abnormities (synechiae, cleft palate, craniofacial dysmorphisms, dental anomaly) and extraoral malformations (skinfold overlying the nails of both halluces, syndactyly, abnormal external genitalia) is presented. The associated malformations addressed to molecular genetic investigations revealing an interferon regulatory factor 6 (IRF6)-related disorder (van der Woude syndrome/popliteal pterygium syndrome). A novel de novo heterozygous mutation in exon 4 of IRF6 gene on chromosome 1q32.2, precisely c.262A > G (p.Asn88Asp), was found. Similarities are discussed with known asparagine missense mutations in the same codon, which may alter IRF6 gene function by reduced DNA-binding ability. A concomitant maternal Xp11.22 duplication involving two microRNA genes could contribute to possible epigenetic effects.ConclusionsOur reported case carrying a novel mutation can contribute to expand understandings of molecular mechanisms underlying synechiae and orofacial clefting and to correct diagnosing of incomplete or overlapping features in IRF6-related disorders. Additional multidisciplinary evaluations to establish the phenotypical extent of the IRF6-related disorder and to address family counseling should not only be focused on the surgical corrections of syngnathia and cleft palate, but also involve comprehensive otolaryngologic, audiologic, logopedic, dental, orthopedic, urological and psychological evaluations.

Genetic Diversity in Key Molecules of Pattern Recognition Receptors (TLR4 and TLR2) in Gastric Cancer

Background: Gastric cancer (GC) is the second most common malignancy and the leading cause of death in Iran.. According to global statistics, these figures are highly worrying highlighting the importance of studies in this field. Given that the role of chronic inflammation in the development of cancer, especially infection-related cancers, such as GC, has been revealed for many years, evaluating the molecules involved in these processes can be helpful. Toll-like-receptors (TLRs) as the greatest family of receptors for inflammation-associated molecular patterns, and the effect of mutations in TLR2 and TLR4 on the pathology of GC has been identified. Considering the results of previous studies and the major role of TLR2 and TLR4 in inflammatory processes of pre-malignancy, in this study, the mutation in the sequence of these genes and its association with GC have been investigated in both laboratory and bioinformatics stages. Materials and Methods: In this study, 30 Helicobacter pylori-positive GC samples were collected and after DNA extraction using Sanger sequencing methods, and subsequently, variant pathogenicity predictions, such as SIFT and PolyPhen, mutation pathogenicity was predicted. Following that, PyMOL was applied to model 3D structures of the wild and mutated receptor. Results: Sanger sequencing data showed a heterozygous mutation in exon 3 of TLR4 c.1061A&gt;G. The modeling crystal structure of the human receptor and LPS complex showed that the variant was far from the TLR4 binding sites with its ligand. Conclusion: The results of this study indicated that mutations in two important genes of the pattern recognition system in Iranian cancer samples have no functional relevance with these two proteins.

Generation of a heterozygous SCN5A knockout human induced pluripotent stem cell line by CRISPR/Cas9 edition

Mutations leading to haploinsufficiency in SCN5A, the gene encoding the cardiac sodium channel Nav1.5 α-subunit, are involved in life-threatening cardiac disorders. Using CRISPR/Cas9-mediated genome edition, we generated here a human induced-pluripotent stem cell (hiPSC) line carrying a heterozygous mutation in exon 2 of SCN5A, which leads to apparition of a premature stop codon. SCN5A-clone 5 line maintained normal karyotype, morphology and pluripotency and differentiated into three germ layers. Cardiomyocytes derived from these hiPSCs would be a useful model for investigating channelopathies related to SCN5A heterozygous deficiency.

Osteogenesis imperfecta: a literature review and a clinical case of a perinatal-lethal type of disease

The article presents the modern views of clinicians and geneticists on one of the most severe genetic disorders of skeletal and connective tissues - osteogenesis imperfecta. The review provided the literature data that showed the incidence rates, genetic heterogeneity of osteogenesis imperfecta, as well as the role of some proteins involved in the construction of bone tissue, as well as a clinical classification of the main types of the disorder. The authors described a clinical case: a girl with typical clinical and radiological manifestations of the rarest of all types of osteogenesis imperfecta - type II (perinatal-lethal, congenital osteogenesis imperfecta, Vrolik’s syndrome). The child’s diagnosis was verified by a parallel DNA sequence analysis which showed a heterozygous mutation in exon 29 (c.1966G&gt; A) of COL1A1 gene not previously described in the literature. It caused the substitution of glycine for serine at position 656. The role of antenatal diagnostics and the importance of medical genetic counselling of the family before planning the next pregnancy due to the existing risk of re-birth of a sick child is outlined. Due to the fact that majority of the patients with the most prognostically unfavourable type II osteogenesis imperfecta, as a rule, die in utero, the described case of observation of the girl with typical clinical and X-ray signs of the disorder for almost 3 months of postpartum period is extremely rare and highly indicative. The detection of the heterozygous mutation in exon 29 (c.1966G &gt; A) of COL1A1 gene by a parallel DNA sequence analysis which was not previously described in the literature gives an additional significance to the described observation.

Application of next generation sequencing in 3 Waardenburg syndrome

Objective:To test the gene sequence of 3 patients with Waardenburg syndrome（WS） using the next generation sequencing technology in order to explore the possible mechanism of molecular genetics. Methods:Medical histories of the family members were collected. Physical examination, audiological evaluation and CT examination were performed. Peripheral blood was collected and DNA was extracted. The exon region of 159 deafness genes, 6 mitochondrial genes and 3 miRNAs of the proband were tested by next generation sequencing. The mutation sites of the possible pathogenic genes were obtained, subsequently, Sanger sequencing verification was performed on the proband and family members. Results:The first proband had a heterozygous mutation in exon 7 of MITF gene（NM_000248）: c.641_643delGAA; The second proband had a heterozygous mutation in exon 10 of MITF gene（NM_001354605）: c.1177-1G>A; The third proband had a heterozygous mutation in exon 5 of PAX3 gene（NM_181457）: c.587_593delCCTCAGC; The parents of the three probands verified by Sanger sequencing that there was no variation at the corresponding sites, and the above mutations were spontaneous mutations. Conclusion:Next generation sequencing can more comprehensively analyze information of the carried status and genetic rules of the disease-associated gene in WS families, and provide guidance for family reproductives.

Compound Heterozygous Myosin 5B (Myo5b) Mutation with Early Onset Progressive Cholestasis and No Intestinal Failure

Background Exome sequencing studies have recently identified novel genes implicated in normal or low GGT pediatric cholestasis including myosin 5B (MYO5B). Case report: We identified novel compound heterozygote mutations in exon 14 and exon 19 of the MYO5B gene in an 18-month-old Indian child with history of fluctuating jaundice and severe pruritus. His liver biopsy showed portal and perivenular fibrosis with focal bridging septa and mild activity. He is currently on UDCA, cholestyramine and vitamin supplements. There is no history of diarrhea. His asymptomatic mother showed heterozygous mutation in exon 19 of the MYO5B gene and his asymptomatic father showed heterozygous mutation in exon 14 of the MYO5B gene. Conclusion: Our report confirms that patients with compound heterozygote mutations in MYO5B develop progressive cholestasis with no intestinal disease.

A rare mutation of thyroid hormone receptor beta gene in thyroid hormone resistance syndrome.

SummaryResistance to thyroid hormone (RTH) is a rare hereditary syndrome with impaired sensitivity to thyroid hormones (TH) and reduced intracellular action of triiodothyronine (T3) caused by genetic variants of TH receptor beta (TRB) or alpha (TRA). RTH type beta (RTHβ) due to dominant negative variants in the TRB gene usually occurs with persistent elevation of circulating free TH, non-suppressed serum TSH levels responding to a thyrotropin-releasing hormone (TRH) test, an absence of typical symptoms of hyperthyroidism and goiter. Here, we present a rare variant in the TRB gene reported for the first time in an Italian patient with generalized RTHβ syndrome. The patient showed elevated TH, with non-suppressed TSH levels and underwent thyroid surgery two different times for multinodular goiter. The genetic test showed a heterozygous mutation in exon 9 of the TRB gene resulting in the replacement of threonine (ACG) with methionine (ATG) at codon 310 (p.M310T). RTHβ syndrome should be considered in patients with elevated TH, non-suppressed TSH levels and goiter.Learning pointsResistance to thyroid hormone (RTH) is a rare autosomal dominant hereditary syndrome with impaired tissue responsiveness to thyroid hormones (TH).Diagnosis of RTH is usually based on the clinical finding of discrepant thyroid function tests and confirmed by a genetic test.RTH is a rare condition that must be considered for the management of patients with goiter, elevation of TH and non-suppressed serum TSH levels in order to avoid unnecessary treatments.

Generation of an iPSC line (UMGWi001-B) from a patient with Floating-Harbor Syndrome (FLHS) carrying a heterozygous SRCAP mutation (p.Arg2444).

Floating-Harbor syndrome (FLHS) is a rare genetic disease caused by mutations in the SRCAP gene. Here, we generated an induced pluripotent stem cell line from gingival fibroblasts of a male patient with a heterozygous mutation in exon 34 of the SRCAP gene (c.7330C>T, p.Arg2444*). The iPSC colonies have an atypical morphology with diffuse borders and disintegrate quickly upon touch. Still, the cell line expresses pluripotency markers and differentiates into three germ layers. The cell line can be used as patient-specific disease model and help elucidate the molecular mechanisms involving SRCAP in the context of FLHS.

VP32.09: Bilateral diaphragmaitc hernia in a case of Cornelia de Lange syndrome

A 38-year-old was sent to our unit for the first trimester scan at 12 weeks pregnancy. The first trimester calculated risk for trisomies was high; b-HCG-0,6 and PAPP-A-0,3. Subsequent amniocentesis revealed normal caryotype 46 XY. Array-comparative genomic hybridisation study didnt reveal any abnormality as well. Our scanning at 12 and 20 weeks revealed severe micrognathia (at 12 weeks) with mandibular spur (20 weeks), dysmorphic facial features such as hypertelorism, long convex philtrum, anteverted nares, depressed nasal bridge, thin lips with downturned lip corners at 20 weeks. Scanning at 20 weeks also revealed bilateral diaphragmatic hernia, stomach and bowel loops located in the left hemithorax, liver located in the right and left hemithorax, anterior displacement of the heart with minimal lateral shift, diaphragm was visible only at its anterior part, small hands with brachydactyly, cleft palate was suspected. After TOP the WES test revealed heterozygous mutation in exon 10 in the NIPBL gene resulting in a frameshift mutation, which is associated with Cornelia de Lange syndrome. Postmortem appearance of the abortus revealed also bushy eyebrows with synophrys, small hands and cleft palate. Diaphragm was presented only at its anterior part. Bilateral diaphragmatic hernia was confirmed. Supporting information can be found in the online version of this abstract Supporting Information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Positional cloning and comprehensive mutation analysis of a Japanese family with lithium-responsive bipolar disorder identifies a novel DOCK5 mutation.

Bipolar disorder (BD) is a severe psychiatric disorder characterized by the recurrence of depressive and manic episodes. Its heritability is high, and many linkage and association studies have been performed. Although various linkage regions and candidate genes have been reported, few have shown sufficient reproducibility, and none have identified the pathogenic genes based on the results of the linkage analysis. To find functional variants that are expected to be rare and have strong genetic effects, we recruited ten healthy individuals, two individuals with unknown status, and six patients with BD or recurrent major depressive disorder (MDD) from a Japanese family consisting of 21 members. We performed a genome-wide linkage analysis using a 100K single-nucleotide polymorphism (SNP) array and microsatellite markers to narrow linkage regions within this family. Subsequently, we performed whole-exome sequencing for two patients with BD to identify genetic mutations in the narrowed linkage regions. Then, we performed co-segregation analysis for DNA variants obtained from the results of the exome sequencing. Finally, we identified a rare heterozygous mutation in exon 31 of DOCK5 (c.3170A>G, p.E1057G). Convergent functional genomics analysis revealed that DOCK5 was listed as one of the biomarkers for mood state and suicidality. Although DOCK5 is still a functionally unknown gene, our findings highlight the possibility of a pathological relationship between BD and DOCK5.

Challenges in the differential diagnosis of multiple endocrine neoplasia syndrome type 1 with isolated family hyperparathyroidism

Multiple endocrine neoplasia type 1 (MEN-1) is the most common cause of the hereditary type of primary hyperparathyroidism (PHPT). If a family type of PHPT is suspected, a dynamic monitoring of patients and their close relatives should be carried out throughout their lives. We present a clinical case of a family in which four members of a pedigree were diagnosed with familial isolated hyperparathyroidism (FIHP). The diagnosis was changed to MEN-1, because it appeared that one of the patients had pancreatic neuroendocrine tumor. Molecular genetic study of MEN1 by direct by means of Sanger sequencing revealed that six family members had a new heterozygous mutation in exon 9: s. 1252 G&gt; T p. D418Y.

Identification of a novel mutation in CRYM in a Chinese family with hearing loss using whole-exome sequencing.

Previous studies have identified ~50 genes that contribute to non-syndromic autosomal dominant sensorineural deafness (DFNA). However, in numerous families with hearing loss, the specific gene mutation remains to be identified. In the present study, the clinical characteristics and gene mutations were analyzed in a Chinese pedigree with hereditary hearing loss. The clinical characteristics of the family members were assessed and a detailed audiology function examination was performed. Whole-exome sequencing (WES) was performed to identify the gene mutation responsible for the hearing loss. Sanger sequencing was used to verify the candidate mutation detected in the family. The family consisted of 31 members, seven of whom were diagnosed with sensorineural deafness of varying degrees. No mutation was identified by the general deafness gene chip. However, a novel heterozygous mutation in exon 3 (c.152C>T; Pro51Leu) of the gene crystallin µ (CRYM) was identified by WES. This result was further verified by Sanger sequencing. Co-segregation of genotypes and phenotypes suggested that this novel mutation was instrumental for the hearing loss/DFNA. In conclusion, the present study identified a novel pathogenic mutation, NM_001888.5(CRYM): c.152C>T(Pro51Leu), associated with DFNA. This mutation has not been reported previously and further functional studies are warranted.