Genomic characterization of peritoneal lavage cytology-positive gastric cancer

Objective: Positive peritoneal lavege cytology(CY1) gastric cancer is featured by dismal prognosis, with high risks of peritoneal metastasis. However, there is a lack of evidence on pathogenic mechanism and signature of CY1and there is a continuous debate on CY1 therapy. Therefore, exploring the mechanism of CY1 is crucial for treatment strategies and targets for CY1 gastric cancer.Methods: In order to figure out specific driver genes and marker genes of CY1 gastric cancer, and ultimately offer clues for potential marker and risk assessment of CY1, 17 cytology-positive gastric cancer patients and 31matched cytology-negative gastric cancer patients were enrolled in this study. The enrollment criteria were based on the results of diagnostic laparoscopy staging and cytology inspection of exfoliated cells. Whole exome sequencing was then performed on tumor samples to evaluate genomic characterization of cytology-positive gastric cancer.Results: Least absolute shrinkage and selection operator(LASSO) algorithm identified 43 cytology-positive marker genes, while Mut Sig CV identified 42 cytology-positive specific driver genes. CD3G and CDKL2 were both driver and marker genes of CY1. Regarding mutational signatures, driver gene mutation and tumor subclone architecture, no significant differences were observed between CY1 and negative peritoneal lavege cytology(CY0).Conclusions: There might not be distinct differences between CY1 and CY0, and CY1 might represent the progression of CY0 gastric cancer rather than constituting an independent subtype. This genomic analysis will thus provide key molecular insights into CY1, which may have a direct effect on treatment recommendations for CY1and CY0 patients, and provides opportunities for genome-guided clinical trials and drug development.

Genetic investigation of the ubiquitin-protein ligase E3A gene as putative target in Angelman syndrome

BACKGROUND Angelman syndrome(AS)is caused by maternal chromosomal deletions,imprinting defects,paternal uniparental disomy involving chromosome 15 and the ubiquitin-protein ligase UBE3A gene mutations.However the genetic basis remains unclear for several patients.AIM To investigate the involvement of UBE3A gene in AS and identifying new potential genes using exome sequencing.METHODS We established a cohort study in 50 patients referred to Farhat Hached University Hospital between 2006 and 2021,with a strong suspicion of AS and absence of chromosomal aberrations.The UBE3A gene was screened for mutation detection.Two unrelated patients issued from consanguineous families were subjected to exome analysis.RESULTS We describe seven UBE3A variants among them 3 none previously described including intronic variants c.2220+14T>C(intron14),c.2507+43T>A(Exon15)and insertion in Exon7:c.30-47_30-46.The exome sequencing revealed 22 potential genes that could be involved in AS-like syndromes that should be investigated further.CONCLUSION Screening for UBE3A mutations in AS patients has been proven to be useful to confirm the diagnosis.Our exome findings could rise to new potential alternative target genes for genetic counseling.

Combined Oxidative Phosphorylation Deficiency-20-Exome as a Diagnostic Implement

Mitochondrial disorders are phenotypically varied, with serious clinical repercussions. Among them, there is the deficiency of combined oxidative phosphorylation of type 20, which occurs due to a defect in the VARS2 gene. This article presents a case of a 2-year-old female with progressive myoclonic epilepsy and psychomotor regression, with refractoriness to multiple anticonvulsants. The diagnosis was only made after the examination was carried out. Therefore, this article highlights the aspects of this rare disease and the importance of the exome for the diagnosis of rare conditions.

Study of pathogenic genes in a pedigree with familial dilated cardiomyopathy

BACKGROUND Dilated cardiomyopathy(DCM)is a genetically heterogeneous cardiac disorder characterized by left ventricular dilation and contractile dysfunction.The substantial genetic heterogeneity evident in patients with DCM contributes to variable disease severity and complicates overall prognosis,which can be very poor.AIM To identify pathogenic genes in DCM through pedigree analysis.METHODS Our research team identified a patient with DCM in the clinic.Through invest-igation,we found that the family of this patient has a typical DCM pedigree.High-throughput sequencing technology,next-generation sequencing,was used to sequence the whole exomes of seven samples in the pedigree.RESULTS A novel and potentially pathogenic gene mutation-ANK2p.F3067L-was discovered.The mutation was completely consistent with the clinical information for this DCM pedigree.Sanger sequencing was used to further verify the locus of the mutation in pedigree samples.These results were consistent with those of high-throughput sequencing.CONCLUSIONS ANK2p.F3067L is considered a novel and potentially pathogenic gene mutation in DCM.

Unique Roberts syndrome with bilateral congenital glaucoma: A case report

BACKGROUND Congenital glaucoma associated with Roberts syndrome(RS)is an unusual and unique condition.No previous report describes this association.A multidisciplinary approach including molecular studies were conducted to reach the final diagnosis.CASE SUMMARY We present a rare case of a 1-wk-old male with RS associated with bilateral congenital glaucoma,left ectopic kidney,and left-hand rudimentary digits.A comprehensive approach was applied by which bilateral non-penetrating glaucoma surgery was performed with good control of intraocular pressure for more than 6 mo.Cytogenetic and molecular testing were conducted and revealed normal measurements.CONCLUSION This report described a case of a male baby with clinical features of RS but with a negative molecular analysis,presenting with left-hand rudimentary digits,bilateral congenital glaucoma,and left ectopic kidney.To the best of our knowledge,this is the first case reported with phocomelia,bilateral congenital glaucoma,and unilateral ectopic kidney.

Histologic features and genomic alterations of primary colorectal adenocarcinoma predict growth patterns of liver metastasis

BACKGROUND Different histological growth patterns(HGPs)of colorectal carcinoma(CRC)liver metastasis are associated with patients’prognosis and response to antiangiogenic therapy.However,the relationship between HGPs of liver metastasis and clinicopathological and genomic characteristics of primary cancer has not been well established.AIM To assess whether certain clinicopathological and genomic features of primary CRC could predict the HGPs of liver metastasis.METHODS A total of 29 patients with paired resections of both primary CRC and liver metastasis were divided into two groups:A(15 cases with desmoplastic liver metastasis)and B(14 cases with replacement liver metastasis).Clinical information was obtained from patients’charts.Mismatch repair proteins,BRAFV600E,and PD-L1 were evaluated by immunohistochemistry.Five cases were selected randomly from each group for whole exome sequencing(WES)analysis.RESULTS In the primary tumor,expanding growth pattern,low tumor budding score(TBS),and Crohn’s disease-like response(CDR)were associated with desmoplastic liver metastasis and better overall survival,whereas infiltrating growth pattern alone of primary carcinoma could predict the replacement liver metastasis and worse overall survival(P<0.05).On WES analysis,primary carcinoma with desmoplastic liver metastasis showed mutations in APC(4/5);TP53(3/5);KRAS,PIK3CA,and FAT4(2/5);BRCA-1,BRCA2,BRAF,and DNAH5(1/5),whereas primary carcinoma with replacement liver metastasis showed mutations in APC and TP53(3/5);KRAS,FAT4,DNH5,SMAD,ERBB2,ERBB3,LRP1,and SDK1(1/5).CONCLUSION The HGPs,TBS,and CDR of primary CRC as well as the presence of specific genetic mutations such as those in PIK3CA could be used to predict the HGPs of liver metastasis,response to therapy,and patients’prognosis.

Unexpected metastasis of intraductal papillary neoplasm of the bile duct without an invasive component to the brain and lungs:A case report

BACKGROUND Despite an expanding number of studies on intraductal papillary neoplasm of the bile duct(IPNB),distant metastasis remains unexplained especially in cases of carcinoma in situ.In the present study,we report a rare and interesting case of IPNB without invasive components that later metastasized to lungs and brain.CASE SUMMARY A 69-year-old male was referred to our hospital due to suspected cholangiocarcinoma.Laboratory tests on admission reported a mild elevation of alkaline phosphatase,γ-glutamyl transpeptidase,and total bilirubin in serum.Endoscopic retrograde cholangiography revealed a filling defect in the common bile duct(CBD)extending to the left hepatic duct.Peroral cholangioscopy delineated a tumor in the CBD that had a papillary pattern.Multidetector computed tomography and magnetic resonance cholangiopancreatography detected partial blockage ot interlude in the CBD leading to cholestasis without evidence of metastasis.Therefore,a diagnosis of IPNB cT1N0M0 was established.Left hepatectomy with bile duct reconstruction was performed.Pathological examination confirmed an intraepithelial neoplasia pattern without an invasive component and an R0 resection achievement.The patient was monitored carefully by regular examinations.However,at 32 mo after the operation,a 26 mm tumor in the lungs and a 12 mm lesion in the brain were detected following a suspicious elevated CA 19-9 level.Video-assisted thoracoscopic surgery of left upper lobectomy and stereotactic radiotherapy are indicated.In addition to histopathological results,a genomic profiling analysis using whole exome sequencing subsequently confirmed lung metastasis originating from bile duct cancer.CONCLUSION This case highlights the important role of genomic profiling analysis using whole exome sequencing in identifying the origin of metastasis in patients with IPNB.

Identification of rare paired box 3 variant in strabismus by whole exome sequencing

AIM： To identify the potentially pathogenic gene variants that contributes to the etiology of strabismus. METHODS： A Chinese pedigree with strabismus was collected and the exomes of two affected individuals were sequenced using the next-generation sequencing technology. The resulting variants from exome sequencing were filtered by subsequent bioinformatics methods and the candidate mutation was verified as heterozygous in the affected proposita and her mother by sanger sequencing. RESULTS： Whole exome sequencing and filtering identified a nonsynonymous mutation Co434G-T transition in paired box 3 （PAX3） in the two affected individuals, which were predicted to be deleterious by more than 4 bioinformatics programs. This altered amino acid residue was located in the conserved PAX domain of PAX3. This gene encodes a member of the PAX family of transcription factors, which play critical roles during fetal development. Mutations in PAX3 were associated with Waardenburg syndrome with strabismus. CONCLUSION： Our results report that the c.434G-T mutation （p.R145L） in PAX3 may contribute to strabismus, expanding our understanding of the causally relevant genes for this disorder.

Apert syndrome diagnosed by prenatal ultrasound combined with magnetic resonance imaging and whole exome sequencing:A case report

BACKGROUND Most cases of Apert syndrome(AS)are found after birth.Cases of AS diagnosed by ultrasound combined with magnetic resonance imaging(MRI)and whole exome sequencing(WES)during pregnancy are rare.CASE SUMMARY We present the case of a 34-year old female patient(gravida 2,para 1)whose fetus was diagnosed with AS during pregnancy.Fetal ultrasound performed at 30,2/7 wk of pregnancy showed abnormalities.MRI and three-dimensional ultrasound performed at 31,1/7 wk of pregnancy showed the possibility of AS.Chromosome examination and core family WES were conducted at 31,5/7 wk of pregnancy.The results showed that FGFR2 in the fetus had a c.755C>G missense mutation in its nucleotide,and AS was confirmed.CONCLUSION This case highlights the importance of imaging examinations.Prenatal ultrasound combined with MRI can identify fetal morphological abnormalities accurately,which can be confirmed by WES.

Missense mutation in DYNC1H1 gene caused psychomotor developmental delay and muscle weakness:A case report

BACKGROUND The DYNC1H1 gene encodes a part of the dynamic protein,and the protein mutations may further affect the growth and development of neurons,resulting in degeneration of anterior horn cells of the spinal cord,and a variety of clinical phenotypes finally resulting in axonal Charcot-Marie-Tooth disease type 20(CMT20),mental retardation 13(MRD13)and spinal muscular atrophy with lower extremity predominant 1(SMA-LED).The incidence of the disease is low,and it is difficult to diagnose,especially in children.Here,we report a case of DYNC1H1 gene mutation and review the related literature to improve the pediatrician’s understanding of DYNC1H1 gene-related disease to make an early correct diagnosis and provide better services for children.CASE SUMMARY A 4-mo-old Chinese female child with adducted thumbs,high arch feet,and epileptic seizure presented slow response,delayed development,and low limb muscle strength.Electroencephalogram showed abnormal waves,a large number of multifocal sharp waves,sharp slow waves,and multiple spasms with a series of attacks.High-throughput sequencing and Sanger sequencing identified a heterozygous mutation,c.5885 G>A(p.R1962H),in the DYNC1H1 gene(NM 001376)of the proband,which was not identified in her parents.Combined with the clinical manifestations and pedigree of this family,this mutation is likely pathogenic based on the American Academy of Medical Genetics and Genomics guidelines.The child was followed when she was 1 year and 2 mo old.The magnetic resonance imaging result was consistent with the findings of white matter myelinated dysplasia and congenital giant gyrus.The extensive neurogenic damage to the extremities was considered,as the results of electromyography showed that the motor conduction velocity and sensory conduction of the nerves of the extremities were not abnormal,and the degree of fit of the children with severe contraction was poor.At present,the child is 80 cm in length and 9 kg in weight,with slender limbs and low muscle strength,and still does not raise her head.She cannot sit or speak.Speech,motor,and mental development was significantly delayed.There is still no effective treatment for this disease.CONCLUSION We herein report a de novo variant of DYNC1H1 gene,c.5885 G>A(p.R1962H),leading to overlapping phenotypes(seizure,general growth retardation,and muscle weakness)of CMT20,MRD13,and SMA-LED,but there is no effective treatment for such condition.Our case enriches the DYNC1H1 gene mutation spectrum and provides an important basis for clinical diagnosis and treatment and genetic counseling.

Efficiency of olaparib in colorectal cancer patients with an alteration of the homologous repair protein

Precision medicine is defined by the administration of drugs based on the tumor's particular genetic characteristics. It is developing quickly in the field of cancer therapy. For example, KRAS, NRAS and BRAF genetic testing demonstrates its efficiency for precision medicine in colorectal cancer(CRC). Besides for these well-known mutations, the purpose of performing larger genetic testing in this pathology is unknown. Recent reports have shown that using the poly ADP ribose polymerase(PARP) inhibitor olaparib in patients with homologous repair enzyme deficiency gave positive clinical results in breast, ovarian and prostate cancers. We have reported here the cases of 2 patients with multi-treated metastatic CRC who underwent somatic and constitutional exome analyses. The analyses revealed a loss of function mutation in a homologous repair enzyme resulting in the loss of heterozygosity for both patients(Check2 for the first patient and RAD51 C for the second one). Both patients were treated with off-label usage of olaparib. While the first patient showed clinical benefit, reduction of carcinoembryonic antigen tumor marker and radiologic response, the second patient quickly presented a progression of the tumor. Additional genetic analyses revealed a frameshift truncating mutation of the TP53BP1 gene in the patient who progressed. Interestingly, deficiency in TP53BP1 was previously described to confer resistance to olaparib in mice breast cancer models. Our findings suggest that exome analysis may be a helpful tool to highlight targetable mutations in CRC and that olaparib may be efficient in patients with a homologous repair deficiency.

Genomic Analysis of 727 Patients with Ehlers-Danlos Syndrome I: Clinical Perspective Relates 23 Genes to a Maternally Influenced Arthritis-Adrenaline Disorder

A novel medical approach for qualifying DNA variants found by whole exome sequencing (WES) facilitates discovery of new gene-disease relationships and emphasizes that DNA change must be correlated with clinical findings before having utility for diagnosis. Delineation of an arthritis-adrenaline disorder (AAD) process qualified variants in 23 genes as diagnostically useful in 727 patients having WES among 1656 with Ehlers-Danlos syndrome (EDS);these results distinguished them from 102 patients who had qualified gene variants among 728 with developmental disability. Excess maternal transmission of AAD by pedigree analysis plus 167 maternally versus 111 paternally transmitted DNA variants and 75 patients with only mitochondrial DNA variants suggest maternal influence on inheritance of AAD and its subsumed EDS types. Genes grouped by impact on different connective tissue elements showed variation in similar numbers of patients with hypermobile or classical EDS, benign joint hypermobility, or predominant dysautonomia: COL7A1, FLG acting on skin in 21 patients;SCN9A/10A/11A, POLG on nerve in 24;COL6A1/A2/A3, COL12 on muscle in 19;COL5A1/A2, FBN1, TGFB2/3, TGFBR1/2 on tissue matrix in 51;COL3A1, VWF on vessel in 18;COL1A1/A2, COL11A1/A2 acting on bone in 15 patients. Each gene group acts through a postulated articulo-autonomic dysplasia cycle to produce reciprocal tissue laxity and dysautonomia findings that transcend EDS types. This same tissue laxity-dysautonomia cycle acts to produce secondary complications in disorders ranging from distinctive connective tissue dysplasias to developmental disorders with hypotonia and acquired conditions with autonomic imbalance. Several altered genes were previously associated with neuromuscular disorders, foreshadowing a large myopathic EDS category that will incorporate many patients with hypermobility. The importance of muscle for joint constraint supports present exercise and future mesenchymal stem cell therapies, whether AAD is genetic or epigenetic from trauma, surgery, inflammation, or aging.

EGFR amplification induces sensitivity to antiEGFR therapy in pancreatic acinar cell carcinoma

Pancreatic acinar cell carcinoma(PACC) is a rare cancer. When the tumor is metastatic, few therapeutic options are available. Precision medicine using next-generation sequencing is defined by the administration of drugs based on the tumor genetic mutations. The usage of precision medicine for finding new therapeutic options for rare cancers is an emerging field. We have reported here the case of a patient bearing a multitreated metastatic PACC. This patient underwent somatic and constitutional exome analyses. The analyses revealed in the liver metastasis an amplification of the EGFR gene. Accordingly, the patient was treated with off-label usage of panitumumab. We observed rapid response with necrosis of the liver metastasis, while no efficacy was observed in the primary tumor. An exome analysis of the primary tumor revealed amplification of HER2 and MET with EGFR amplification. Such amplifications are known as a resistance mechanism to anti EGFR therapy. Our results suggest that exome analysis may be helpful to highlight targets in rare cancers, such as PACC. EGFR amplification in this pathology should be determined and could be used as a biomarker to propose anti EGFR therapy.

A Chinese family with Axenfeld-Rieger syndrome:report of the clinical and genetic findings

AIM： To describe a Chinese family affected by a severe form of Axenfeld-Rieger syndrome （ARS） and characterize the molecular defect in PITX2 in the family. METHODS： Patients presented with typical ARS from a Chinese family were investigated. We performed genome- wide linkage scan and exome sequencing to identify the pathogenic mutations, Candidate mutations were verified for co-segregation in the whole pedigree using Sanger sequencing, Real-time polymerase chain reaction （RT- PCR） and Western blotting were performed to verify the expression of the pathogenic gene. RESULTS： Genome-wide linkage and exome sequencing analyses showed PITX2 as the disease candidate gene. A〉G substitution at position -11 of 3＇ss of exon 5 （IVS5- 11A〉G） that co-segregated with the disease phenotype was discovered in the family. The PITX2 messenger ribonucleic acid and protein levels were about 50% lower in patients with ARS than in unaffected family members in the family, CONCLUSION： Our findings implicate the first intronic mutation of the PITX2 gene in the pathogenesis of a severe form of ARS in a Chinese family. This study highlights the importance of a systematic search for intronic mutation in ARS cases for which no mutations in the exons of PITX2 have been found.

Identification of a Novel COL17A1 Compound Heterozygous Mutation in a Chinese Girl with Non-Herlitz Junctional Epidermolysis Bullosa

Summary:Non-Herlitz junctional epidermolysis bullosa(JEB-nH),an autosomal recessive bullous genodermatosis,is characterized by generalized skin blistering from birth onward,dental anomalies,universal alopecia and nail dystrophy.The underlying defect is mutation of the COLI7AI gene encoding the type XVⅡcollagen,resulting in losing structure for attachment of basal epithelial cells to the matrix.In present study,we described one case of congenitally affected female child aged 10 years,with skin blistering.Dermatologic examination revealed sparse,mild blisters on the face and hand,with profound enamel pitting of the teeth.Skin biopsy from proband's bullous skin displayed subepidermal bulla formation without acantholysis.The immunofluorescence of anti-type XVⅡcollagen antibody staining showed loss of type XVⅡcollagen staining at the basement membrane zone.A combination of whole exome sequencing(WES)and Sanger sequencing revealed the novel heterozygous mutations(C.4324C>T;p.Q1442^*and C.I 834G>C;p.G612R)in COLI7AI gene,which could be associated with the observed JEB-nH.One allele had a novel nonsense mutation(c.4324C>T;p.Q1442^*),resulting in nonsense-mediated mRNA decay and truncated collagen XVⅡ;the other allelc had a novel misscnse mutation of c.1834G>C;p.G612R in exon 22,causing a glycine-to-arginine substitution in the Gly-X-Y triple helical repeating motifs and decreasing the thermal stability of collagen XVⅡ.Our findings indicate that the genetic test based on WES can be useful in diagnosing JEB-nH patients.The novel pathogenic mutations identified would further expand our understanding of the mutation spectrum of COLI7AI gene in association with the inherited blistering diseases.

Impact of next-generation sequencing on molecular diagnosis of inherited non-syndromic hearing loss

Hearing loss is one of the most common birth defects,with inherited genetic defects play an important role,contributing to about 60%of deafness occurring in infants.However,hearing impairment is genetically heterogeneous,with both common and rare forms occurring due to mutations in estimated 500 genes.Due to the large number and presumably low mutation frequencies of those genes,it would be highly expensive and time-consuming to address this issue by conventional gene-by-gene Sanger sequencing.Next-generation sequencing is a revolutionary technology that allows the simultaneous screening of mutations in a large number of genes.It is cost effective compared to classical strategies of linkage analysis and direct sequencing when the number or size of genes is large,and thus has become a highly efficient strategy for identifying novel causative genes and mutations involved in heritable disease.In this review, we describe major NGS methodologies currently used for genetic disorders and highlight applications of these technologies in studies of molecular diagnosis and the discovery of genes implicated in non-syndromic hearing loss.

Exome analysis for Cronkhite-Canada syndrome: A case report

BACKGROUND Cronkhite-Canada syndrome(CCS)is a rare,non-genetic disorder characterized by multiple gastrointestinal polyps,and ectodermal lesions such as alopecia,fingernail atrophy,and skin mucosal pigmentation.Unfortunately,the pathogenesis of CCS is currently unknown.CASE SUMMARY Here,we describe the case of an elderly female with diarrhea,fatigue,and hair loss,who experienced abdominal pain for over half a year and was found to have multiple gastrointestinal polyps.She was diagnosed with CCS and was treated with albumin supplementation and prednisone,and her electrolyte imbalance was corrected.Following treatment,her symptoms significantly improved.To elucidate the role of potential genetic events in the pathogenesis of CCS,we performed exome sequencing using an extract of her colorectal adenoma.CONCLUSION Our data revealed multiple somatic mutations and copy number variations.Our findings provide a novel insight into the potential mechanisms of CCS etiology.

Hepatocyte nuclear factor 1B mutation in a Chinese family with renal cysts and diabetes syndrome:A case report

BACKGROUND Renal cysts and diabetes(RCAD)syndrome is an autosomal dominant diabetic renal disease.Precise molecular diagnosis of RCAD syndrome has proven valuable for understanding its mechanism and personalized therapy.CASE SUMMARY A RCAD patient and her family were studied to investigate potential responsible genes by the whole exome sequencing(WES).Candidate pathogenic variants were validated by Sanger sequencing.The clinical characteristics of RCAD patient were collected from medical records.Unlike those typical RCAD patients,we observed renal manifestation and prediabetes phenotype,but not reproductive organ phenotype and hypomagnesaemia.A novel 7-bp deletion mutation in exon 4 of the hepatocyte nuclear factor 1B,NM_000458:c.882_888del(p.V294fs),was identified by WES and confirmed by Sanger sequencing.CONCLUSION This novel mutation identified in a Chinese family with RCAD syndrome might be the molecular pathogenic basis of this disorder.

Whole exome sequencing identifies an AMBN missense mutation causing severe autosomal-dominant amelogenesis imperfecta and dentin disorders

Tooth development is a complex process that involves precise and time-dependent orchestration of multiple genetic, molecular,and cellular interactions. Ameloblastin(AMBN, also named "amelin" or "sheathlin") is the second most abundant enamel matrix protein known to have a key role in amelogenesis. Amelogenesis imperfecta(AI [MIM: 104500]) refers to a genetically and phenotypically heterogeneous group of conditions characterized by inherited developmental enamel defects. The hereditary dentin disorders comprise a variety of autosomal-dominant genetic symptoms characterized by abnormal dentin structure affecting either the primary or both the primary and secondary teeth. The vital role of Ambn in amelogenesis has been confirmed experimentally using mouse models. Only two cases have been reported of mutations of AMBN associated with non-syndromic human AI. However, no AMBN missense mutations have been reported to be associated with both human AI and dentin disorders.We recruited one kindred with autosomal-dominant amelogenesis imperfecta(ADAI) and dentinogenesis imperfecta/dysplasia characterized by generalized severe enamel and dentin defects. Whole exome sequencing of the proband identified a novel heterozygous C-T point mutation at nucleotide position 1069 of the AMBN gene, causing a Pro to Ser mutation at the conserved amino acid position 357 of the protein. Exfoliated third molar teeth from the affected family members were found to have enamel and dentin of lower mineral density than control teeth, with thinner and easily fractured enamel, short and thick roots, and pulp obliteration. This study demonstrates, for the first time, that an AMBN missense mutation causes non-syndromic human AI and dentin disorders.

Impact of exome sequencing in inflammatory bowel disease

Approaches to understanding the genetic contribution to inflammatory bowel disease(IBD)have continuously evolved from family-and population-based epidemiology,to linkage analysis,and most recently,to genome-wide association studies(GWAS).The next stage in this evolution seems to be the sequencing of the exome,that is,the regions of the human genome which encode proteins.The GWAS approach has been very fruitful in identifying at least 163 loci as being associated with IBD,and now,exome sequencing promises to take our genetic understanding to the next level.In this review we will discuss the possible contributions that can be made by an exome sequencing approach both at the individual patient level to aid with disease diagnosis and future therapies,as well as in advancing knowledge of the pathogenesis of IBD.