Frameshift Mutation In Exon Research Articles

Twenty patients including 7 probands with autosomal dominant cutis laxa confirm clinical and molecular homogeneity

BackgroundElastin gene mutations have been associated with a variety of phenotypes. Autosomal dominant cutis laxa (ADCL) is a rare disorder that presents with lax skin, typical facial characteristics, inguinal hernias, aortic root dilatation and pulmonary emphysema. In most patients, frameshift mutations are found in the 3’ region of the elastin gene (exons 30-34) which result in a C-terminally extended protein, though exceptions have been reported.MethodsWe clinically and molecularly characterized the thus far largest cohort of ADCL patients, consisting of 19 patients from six families and one sporadic patient.ResultsMolecular analysis showed C-terminal frameshift mutations in exon 30, 32, and 34 of the elastin gene and identified a mutational hotspot in exon 32 (c.2262delA). This cohort confirms the previously reported clinical constellation of skin laxity (100%), inguinal hernias (51%), aortic root dilatation (55%) and emphysema (37%).ConclusionADCL is a clinically and molecularly homogeneous disorder, but intra- and interfamilial variability in the severity of organ involvement needs to be taken into account. Regular cardiovascular and pulmonary evaluations are imperative in the clinical follow-up of these patients.

Novel frameshift mutation in TRPS1 in a ukrainian patient with trichorhinophalangeal syndrome type I

Trichorhinophalangeal syndrome (TRPS) type I is a rare autosomal dominant disorder, caused by mutations in the TRPS1 gene. It is characterized by slowly growing hair, craniofacial manifestations and orthopedic abnormalities. We present a 17-year-old female of Ukrainian origin who presented to the hair clinic with the complaint of hair loss. Further examination revealed the presence of craniofacial features characteristic for TRPS type I. Sequence analysis of the TRPS1 gene revealed a novel c. 2396_2397 insG frameshift mutation in exon 5, leading to a premature stop at codon 800. This case underlines the importance of the hair phenotype to the diagnosis of this syndrome and emphasizes the fact that when encountered with a severe alopecia in young age, the possibility of a congenital hair disease should always be borne in mind.

Severe short stature due to 3-M syndrome with a novel OBSL1 gene mutation

3-M syndrome is an underdiagnosed autosomal recessive disorder characterized by severe pre- and postnatal growth retardation with minimal dysmorphic features and distinguishing radiological findings. We report a patient who was first admitted at 7.5 years of age. He was born to consanguineous parents with a birth weight of 2250 g. Physical examination revealed a severe short stature (height, 95 cm; SD score -5.64) and minimal dysmorphic features. Biochemistry, endocrine work-up, and karyotype were normal. Reevaluation at 16.5 years of age revealed a height of 128.5 cm (SD score -5.27), prominent forehead, anteverted nasal openings, fleshy nasal tip, full lips, malar hypoplasia, hyperlordosis, prominent heels, testicular volumes 8-10 mL, and pubic hair consistent with Tanner stage II. Growth hormone trial for a year resulted in inadequate height gain (3 cm). The diagnosis of 3-M syndrome was made upon typical findings (thin long bones with diaphyseal narrowing and tall lumbar vertebrae) in a recent skeletal survey. Genetic analysis disclosed a homozygote frame shift mutation in exon 2: c.457_458delinsT resulting in p.Gly153fs.

TGFB2 mutations cause familial thoracic aortic aneurysms and dissections associated with mild systemic features of Marfan syndrome

A predisposition for thoracic aortic aneurysms leading to acute aortic dissections can be inherited in families in an autosomal dominant manner. Genome-wide linkage analysis of two large unrelated families with thoracic aortic disease, followed by whole exome sequencing of affected relatives, identified causative mutations in TGFB2. These mutations, a frameshift mutation in exon 6 and a nonsense mutation in exon 4, segregated with disease with a combined LOD score of 7.7. Sanger sequencing of 276 probands from families with inherited thoracic aortic disease identified two additional TGFB2 mutations. TGFB2 encodes the transforming growth factor beta-2 (TGF-β2) and the mutations are predicted to cause haploinsufficiency for TGFB2, but aortic tissue from cases paradoxically shows increased TGF-β2 expression and immunostaining. Thus, haploinsufficiency of TGFB2 predisposes to thoracic aortic disease, suggesting the initial pathway driving disease is decreased cellular TGF-β2 levels leading to a secondary increase in TGF-β2 production in the diseased aorta.

Hb Filottrano [codon 120 (–A)]: A Novel Frameshift Mutation in Exon 3 of the β-Globin Gene Causing Dominantly Inherited β-Thalassemia Intermedia

We report a novel frameshift mutation in exon 3 of the β-globin gene, that, in the heterozygous state, leads to a β-thalassemia intermedia (β-TI) phenotype (marked anemia, splenomegaly, hyperbilirubinemia, jaundice, unbalanced synthesis of α/non-α chains in a 34-year-old Italian woman. This frameshift mutation, due to the deletion of the first nucleotide (–A) at codon 120, results in a β-globin chain that is elongated to 156 amino acid residues. These highly unstable abnormal chains precipitate in the erythroblasts as inclusion bodies, thus causing inefficient erythropoiesis and ultimately resulting in the observed dominant clinical phenotype.

A nonconservative amino acid change in the UPF3B gene in a patient with schizophrenia

Szyszka, Paulina; Sharp, Sally I.; Dedman, Alexandra; Gurling, Hugh M.D.; McQuillin, Andrew Author Information

Primary Hyperparathyroidism in MEN1 Patients

To identify the optimal surgical strategy for multiple endocrine neoplasia type 1 (MEN1)-related primary hyperparathyroidism (pHPT). To describe the course of postoperative hypoparathyroidism and to assess whether genotype is associated with persistent/recurrent pHPT. Surgery is the preferred treatment in MEN1-related pHPT, but the surgical procedure of choice is still uncertain. This retrospective cohort study was performed at the Departments of Endocrinology of the University Medical Centers of Utrecht and Nijmegen, the Netherlands. Patients were selected from the Dutch MEN1 database, including all patients 16 years or older treated for MEN1 from 1990 to 2009. Data were collected by medical record review. Seventy-three patients underwent parathyroid surgery. Persistent/recurrent pHPT occurred in 53% after less than 3 parathyroids resected (<SPTX), 17% after subtotal resection (SPTX), and 19% after total resection with autotransplantation (TPTX). Persistent (≥6 months) postoperative hypoparathyroidism occurred in 24% after <SPTX, 39% after SPTX, and 66% after TPTX. Median duration of hypoparathyroidism was 1.5 years, in 65% successful cessation of vitamin D/calcium was possible, even after more than 10 years. After <SPTX, patients with nonsense or frameshift mutations in exons 2, 9, and 10 had a significantly lower risk of persistent/recurrent pHPT than patients with other mutations. After SPTX/TPTX persistence/recurrence did not differ with genotype. After SPTX/TPTX persistence/recurrence was more frequent (P = 0.07) in patients without bilateral transcervical thymectomy (TCT). SPTX with bilateral TCT is the procedure of choice for MEN1-related pHPT. Genotype seems to affect the chance of recurrence. Postoperative hypoparathyroidism lasting 6 months or more should not be considered permanent in MEN1.

α+-Thalassemia Trait Caused by a Frameshift Mutation in Exon 2 of the α2-Globin Gene [HBA2 c.244delT

We report a case of α+-thalassemia (α+-thal) trait caused by a novel frameshift mutation in exon 2 of the α2-globin gene, specifically a deletion of a single nucleotide at amino acid codon 81 [HBA2 c.244delT]. The mutation results in a premature termination of translation at codon 83.

A knockout mutation in the lignin biosynthesis gene CCR1 explains a major QTL for acid detergent lignin content in Brassica napus seeds

Seed coat phenolic compounds represent important antinutritive fibre components that cause a considerable reduction in value of seed meals from oilseed rape (Brassica napus). The nutritionally most important fibre compound is acid detergent lignin (ADL), to which a significant contribution is made by phenylpropanoid-derived lignin precursors. In this study, we used bulked-segregant analysis in a population of recombinant inbred lines (RILs) from a cross of the Chinese oilseed rape lines GH06 (yellow seed, low ADL) and P174 (black seed, high ADL) to identify markers with tight linkage to a major quantitative trait locus (QTL) for seed ADL content. Fine mapping of the QTL was performed in a backcross population comprising 872 BC(1)F(2) plants from a cross of an F(7) RIL from the above-mentioned population, which was heterozygous for this major QTL and P174. A 3:1 phenotypic segregation for seed ADL content indicated that a single, dominant, major locus causes a substantial reduction in ADL. This locus was successively narrowed to 0.75cM using in silico markers derived from a homologous Brassica rapa sequence contig spanning the QTL. Subsequently, we located a B. rapa orthologue of the key lignin biosynthesis gene CINNAMOYL CO-A REDUCTASE 1 (CCR1) only 600kbp (0.75cM) upstream of the nearest linked marker. Sequencing of PCR amplicons, covering the full-length coding sequences of Bna.CCR1 homologues, revealed a locus in P174 whose sequence corresponds to the Brassica oleracea wild-type allele from chromosome C8. In GH06, however, this allele is replaced by a homologue derived from chromosome A9 that contains a loss-of-function frameshift mutation in exon 1. Genetic and physical map data infer that this loss-of-function allele has replaced a functional Bna.CCR1 locus on chromosome C8 in GH06 by homoeologous non-reciprocal translocation.

Lack of expression of SERPINF1, the gene coding for pigment epithelium-derived factor, causes progressively deforming osteogenesis imperfecta with normal type I collagen

Osteogenesis imperfecta (OI) is a clinically heterogeneous heritable connective tissue disorder, characterized by low bone mass and reduced strength, which result in susceptibility to fracture and bone deformities. In most cases it is caused by dominant mutations in type I collagen genes, COL1A1 and COL1A2. Recessive forms, which collectively account for approximately 5% of cases of osteogenesis imperfecta detected in North America and Europe, are caused instead by mutations in various genes coding for proteins involved in collagen posttranslational modifications, folding, and secretion. A novel disease locus, SERPINF1, coding for pigment epithelium-derived factor (PEDF), has been found recently. In SERPINF1 mutants described so far, synthesis, posttranslational modification, and secretion of type I collagen were reported to be normal. Here we describe three siblings born to consanguineous parents, who show an initially mild and then progressively worsening form of OI with severe deformities of the long bones. They are homozygous for a frameshift mutation in exon 4 of the SERPINF1 gene, which leads to lack of the transcription/translation product, likely a key factor in bone deposition and remodeling. Synthesis and secretion of type I collagen are normal. Clinical, radiographic, histological, and histomorphometric data from the proband are reminiscent of the distinctive features of type VI OI.

Val17Ile Single Nucleotide Polymorphisms Similarly as Ala15Thr Could be Related to the Lower Secretory Dynamics of PAI-1 Secretion – Theoretical Evidence

Plasminogen activator inhibitor (PAI-1) is a fast acting inhibitor of tissue and urokinase plasminogen activators (tPA and uPA). In that way PAI-1 regulates proteolytic activity of many physiological and pathological processes [1-3]. PAI-1 plays an important role in blood coagulation controlling clot lysis which is triggered by tPA activated plasminogen [4]. Only two types of mutations are reported to be associated with PAI-1; one is the frame-shift mutation in exon 4 of PAI-1 gene resulting in a truncated nonfunctional protein and in complete PAI-1 deficiency. The other SNP causes Ala15Thr mutation in the signal peptide. A literature search revealed five variants of polymorphisms during a study of over one thousand individuals. Two are associated with thrombophilia (765 4G/5G and -844 A>G, in the promoter), risk of myocardial infarction and postoperative deep venous thrombosis related to higher than normal levels of PAI-1. The other SNPs associated with PAI-1 deficiency are Ala15Thr, Val17Ile and they are located in the central hydrophobic core of the PAI-1 signal peptide of PAI-1 and Asn195Ile in the 'A' β sheet of the PAI-1. We have analyzed two SNPs not reported to be associated with PAI-1 deficiency. Our analysis suggests that Val17Ile PAI-1 variant might cause slower PAI-1 secretion leading to the deficiency at time and place where it is needed in a similar way as for Ala15Thr SNP. The Asn195Ile mutant may be more stable only as latent form thus no PAI-1 deficiency is expected in this mutant.

Novel mutation in ATP13A2 widens the spectrum of Kufor‐Rakeb syndrome (PARK9)

Kufor-Rakeb syndrome (KRS) is a rare autosomal recessive inherited juvenile parkinsonian syndrome caused by mutations in ATP13A2. We describe six patients from a consanguineous Greenlandic Inuit family, homozygous for a novel frame-shift mutation in exon 22 of ATP13A2 (c.2473C>AA, p.Leu825AsnfsX32). Disease onset varied from 10 to 29 years of age, the latest reported, and the clinical features were highly variable within a wide spectrum of an extrapyramidal-pyramidal syndrome with cognitive/psychiatric features. Ataxia was seen in two patients and axonal neuropathy in one, features not previously related to KRS. Dopamine transporter scans showed symmetrical, severely reduced uptake in striatum in two patients. Magnetic resonance imaging was without atrophy in one patient despite disease duration of 17 years, and cerebral and cerebellar atrophy was seen in another patient after 4 years of disease duration. The molecular pathogenic mechanisms of ATP13A2 mutations are discussed. The observation that the mutant transcript is not degraded by nonsense-mediated RNA decay and the fact that none of the eight heterozygous carriers from the family have KRS symptoms suggest that the mutant protein does not interfere and destroy the function of the wild-type ATP13A2 protein.

Novel mutations in NEB cause abnormal nebulin expression and markedly impaired muscle force generation in severe nemaline myopathy

BackgroundNemaline myopathy (NM) is a congenital muscle disease associated with weakness and the presence of nemaline bodies (rods) in muscle fibers. Mutations in seven genes have been associated with NM, but the most commonly mutated gene is nebulin (NEB), which is thought to account for roughly 50% of cases.ResultsWe describe two siblings with severe NM, arthrogryposis and neonatal death caused by two novel NEB mutations: a point mutation in intron 13 and a frameshift mutation in exon 81. Levels of detectable nebulin protein were significantly lower than those in normal control muscle biopsies or those from patients with less severe NM due to deletion of NEB exon 55. Mechanical studies of skinned myofibers revealed marked impairment of force development, with an increase in tension cost.ConclusionsOur findings demonstrate that the mechanical phenotype of severe NM is the consequence of mutations that severely reduce nebulin protein levels and suggest that the level of nebulin expression may correlate with the severity of disease.

A new de novo mutation in the GCK gene causing MODY2

Analysis of glucokinase (GCK) gene in a 15-year-old male identified a new frameshift mutation in exon 4 caused by a heterozygous guanine deletion at position 382 (c.382delG, p.E128Xfs). No mutation was detected in the parents. Polymorphic markers’ study excluded false paternity indicating that c.382delG is a novel de novo mutation.

Further evidence for a marfanoid syndrome with neonatal progeroid features and severe generalized lipodystrophy due to frameshift mutations near the 3′ end of the FBN1 gene

We report on a 20-year-old man who presented in infancy with severe generalized lipodystrophy with a progeroid appearance and some Marfanoid features. He subsequently was diagnosed with bilateral lens subluxations at the age of 16 years which prompted analysis of the FBN1 gene. This analysis showed him to have a novel heterozygous, de novo, c.8156_8175del, p.Lys2719ThrfsX12, frameshift mutation in exon 64 of his FBN1 gene. His phenotype is similar to a patient described by Graul-Neumann et al. [2010] who was found to have a de novo, heterozygous, c.8155_8156del deletion in exon 64 of FBN1. Both mutations result in a truncated protein with an extremely charged C-terminus, containing two positive and four negative charges in the last eight amino acids. This most likely has a profound impact on protein–protein interactions, which are very important in the extracellular matrix. The similarities in the phenotypes, and overlapping molecular defects, provides further evidence that the phenotype with features of Marfan syndrome with neonatal progeroid syndrome-like lipodystrophy is a distinct clinical entity due to frameshift mutations in exon 64 of the FBN1 gene.

ATM Gene Point Mutation and Frameshift Mutation Are Found In High-Risk, Untreated Chronic Lymphocytic Leukemia Patients with Interstitial Deletion of Chromosome 11q and Uniparental Disomy of Chromosome 11q

AbstractAbstract 2420 Introduction:Interstitial deletion of chromosome 11q (11q-) detected by fluorescence in situ hybridization (FISH) is an unfavorable prognostic marker in chronic lymphocytic leukemia (CLL). CLL patients with 11q- often have younger age of onset, bulky lymphadenopathy, and poorer overall survival. The ataxia-telangiectasia mutated (ATM) gene, which encodes a protein kinase central to DNA damage response, is thought to be the critical gene in CLL 11q- through loss of ATM function. A subgroup of CLL patients with 11q- has been shown by other investigators to have a mutation in the remaining ATM allele, supporting a loss-of-function hypothesis. In an ongoing study, we are using SNP-based whole genome copy number variation (CNV) analysis to characterize in detail the 11q deletions in CLL patients. In addition, we have reported uniparental disomy (UPD) of 11q in CLL patients negative for FISH abnormalities. Here we report direct DNA sequence analysis of the ATM gene in CLL patients with 11q- and with UPD of 11q. Patients and Methods:We performed CNV analysis and ATM sequencing on 10 patients aged 29–67 with early-intermediate stage, untreated CLL who had high risk for disease progression based on molecular and immunophenotypic markers. Eight patients had 11q- and 2 patients had UPD of 11q. CLL cells and normal cells were separated from patient peripheral blood samples by immunomagnetic beads. CNV analysis was performed on purified genomic DNA from CLL and normal cells for each patient to distinguish acquired copy number changes in malignant cells from polymorphic CNVs in the human genome. We used the Illumina 660w-quad beadchip, a SNP-based microarray for CNV analysis. CNV data was analyzed by CNV partition and PennCNV software. DNA sequence analysis of the ATM gene was performed by the dideoxy chain termination method using an ABI 3730 DNA Analyzer. All coding regions of the ATM gene (exons 4–65) and associated splice site junctions were amplified by PCR using purified genomic DNA from CLL cells. DNA sequence of the PCR products was determined on both strands. Sequence data was analyzed by Sequencher software. Results:In the 8 CLL patients with 11q−, CNV analysis demonstrates hemizygous interstitial deletions that vary from 980 Kb to 43.2 Mb. All deletions include the region of the ATM gene at 11q22.3. Two out of these 8 patients have a mutation in the residual ATM allele. One patient (CLL010) has a point mutation in exon 61 of ATM (c.8600G>A (gly2867glu)) that likely involves the substrate-binding region of the PI3-kinase domain. One patient (CLL029) has a frameshift mutation in exon 12 of ATM (c.1401_1405delCAAGA; asp467fs) that causes a premature stop signal at codon 484, presumably resulting in a truncated protein. In the 2 CLL patients with UPD of 11q, CNV analysis demonstrates copy-neutral loss of heterozygosity that extends from either 11q12.1 (CLL008) or 11q13.1 (CLL009) to the terminus of 11q. Both patients with UPD of 11q display homozygous mutation of the ATM gene. One patient (CLL008) has a point mutation in exon 58 of ATM (c.8161G>A (asp2721asn)) that likely involves the ATP binding site in the catalytic domain. One patient (CLL009) has a frameshift mutation in exon 24 of ATM (c.3238_3247del10bp/ins11bp; asp1080fs) that creates a premature stop signal at codon 1095, presumably resulting in a truncated protein. Conclusions:We report a new finding that ATM gene mutation occurs in CLL patients with UPD of 11q. Our study further expands observations reported by others concerning the role of ATM mutations in CLL. ATM mutations that we characterized include point mutations that may interfere with kinase activity and frameshift mutations that may result in a truncated ATM protein. Our sequence analysis supports a loss-of-function mechanism for ATM in a subgroup of high-risk, untreated CLL patients. The absence of detectable ATM mutations in the majority of CLL patients with 11q- may imply the existence of hidden ATM mutations not found by our targeted exon sequencing approach or epigenetic mechanisms that result in loss of gene expression. The finding that untreated CLL patients with UPD of 11q have homozygous ATM mutation supports a clonal selection hypothesis for identical alleles of mutated ATM in the absence of mutagenic chemotherapy. Selection of a CLL subclone with mutated ATM may confer a proliferative advantage through increased cell division and/or resistance to apoptosis following DNA damage. Disclosures:Zent: Genzyme: Research Funding; Genentech: Research Funding; Novartis: Research Funding; G.S.K.: Research Funding.

Novel deleterious mutation in the F12 gene in a Korean family with severe coagulation factor XII deficiency

Coagulation factor XII (FXII) is involved in the initiation of blood coagulation, fibrinolysis, complement systems, and bradykinin generation. Hereditary deficiency of FXII is caused by mutations in the F12 gene. In this report, we describe a Korean family with severe FXII deficiency from F12 mutations. The proband was a 46-year-old woman and was shown to have a markedly prolonged activated partial thromboplastin time at 126.7 s (reference range, 29-42 s) on routine health checkup. She had no history of bleeding tendency. Complete correction of prolonged activated partial thromboplastin time on mixing test prompted us to perform factor assays, which revealed a markedly decreased FXII activity (<0.5%; below the detection limit). Direct sequencing analyses for F12 showed that the proband was compound heterozygous for two deleterious mutations, c.249delG (p.Q83HfsX12) and c.405C>A (p.C135X). Family study showed that her sister with prolonged activated partial thromboplastin time at 83.8 s and FXII activity less than 0.5% was also compound heterozygous for the mutations. Q83HfsX12 was a novel frameshift mutation in exon 4 of F12, and C135X is a nonsense mutation previously reported in a Korean patient who was homozygous for the mutation. Thus, the C135X mutation is a recurrent mutation in Korean individuals with FXII deficiency, potentially with a founder effect.

Familial Glucocorticoid Resistance Caused by a Novel Frameshift Glucocorticoid Receptor Mutation

ABSTRACT Context Familial glucocorticoid resistance is a rare condition with a typical presentation of women with hirsutism and hypertension, with or without hypokalemia. Objective The aim was to determine the cause of apparent glucocorticoid resistance in a young woman. Patients and Methods We studied a family with a novel glucocorticoid receptor (GR) mutation and a surprisingly mild phenotype. Their discovery resulted from serendipitous measurement of serum cortisol with little biochemical or clinical evidence for either hyperandrogenism or mineralocorticoid excess. Results The causative mutation was identified as a frameshift mutation in exon 6. Transformed peripheral blood lymphocytes were generated to analyze GR expression in vitro. Carriers of the mutation had less full-length GR, but the predicted mutant GR protein was not detected. However, this does not exclude expression in vivo, and so the mutant GR (D612GR) was expressed in vitro. Simple reporter gene assays suggested that Δ612GR has dominant negative activity. Δ612GR was not subject to ligand-dependent Ser211 phosphorylation or to ligand-dependent degradation. A fluorophore-tagged construct showed that Δ612GR did not translocate to the nucleus in response to ligand and retarded translocation of the wild-type GR. These data suggest that Δ612GR is not capable of binding ligand and exerts dominant negative activity through heterodimerization with wild-type GR. Conclusion Therefore, we describe a novel, naturally occurring GR mutation that results in familial glucocorticoid resistance. The mutant GR protein, if expressed in vivo, is predicted to exert dominant negative activity by impairing wild-type GR nuclear translocation.

Early appearance of hypokalemia in Gitelman syndrome

Inactivating mutations in the SLC12A3 gene that encodes the thiazide-sensitive co-transporter causes Gitelman syndrome. The main features of this syndrome include normal or low blood pressure, hypokalemia, metabolic alkalosis, hypomagnesemia, hypocalciuria, and hyperreninemia. These patients are at low risk for preterm birth and do not present with symptoms before school age. As a consequence, the condition is usually diagnosed in late childhood or in adult life. We report on four patients, two pairs of prematurely born twins, in whom hypokalemia was demonstrated early in life. In these children, a tendency towards hypokalemia was first noted during the third week of life. Overt hypokalemia subsequently appeared associated with normal blood pressure, hypochloremia, hyperreninemia, and an inappropriately high fractional excretion of potassium and chloride. Molecular biology studies failed to detect mutations in the SLC12A1, KCNJ1, and CLCNKB genes responsible for the Bartter syndromes type I, II and III, respectively. Compound heterozygous mutations in the SLC12A3 gene were detected in both pairs of twins: a frameshift mutation in exon 10 (c.1196_1202dup7bp), leading to the truncated protein p.Ser402X, and a missense mutation in exon 11, p.Ser475Cys (c.1424C>G) in the first pair; two missense mutations, p.Thr392Ile (c.1175C>T) in exon 9 and p.Ser615Leu in exon 15 (c.1844C>T), in the second pair. In conclusion, the diagnosis of Gitelman syndrome deserves consideration in infants with unexplained hypokalemia.

Germline mutation of the E-cadherin gene in three sibling cases with advanced gastric cancer: clinical consequences for the other family members

Germline mutations in the E-cadherin (CDH1) gene have been found in families with hereditary diffuse gastric cancer (HDGC). These families are characterized by a highly penetrant susceptibility to diffuse gastric cancer with an autosomal dominant pattern of inheritance. We describe the clinical presentation of three sibling cases with advanced gastric cancer, the way of confirming the suspicion of underlying HDGC and the clinical management of the other healthy family members. Screening for CDH1 germline mutation was carried out by denaturing high-performance liquid chromatography and automated DNA sequencing. The clinical suspicion of HDGC has been confirmed by identifying a frameshift mutation in exon 9 (1302_1303insA, 1306_1307delTT) of the E-cadherin gene. Eight of nine tested family members were positive for the CDH1 germline mutation. Prophylactic laparoscopic gastrectomies were performed in five mutation carriers. After pathological examination, we could identify intramucosal malignant signet-ring cell carcinoma in all resected stomachs. This report underlines that prophylactic gastrectomy remains the only option to eliminate the high risk for gastric cancer in CDH1 mutation carriers.