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We present data from our clinical department's experience with chromosomal microarray analysis (CMA) regarding the diagnostic utility of 1 or 2 long contiguous stretches of homozygosity (LCSHs) in an outbred population. The study group consisted of 2,110 consecutive patients from 2011 to 2014 for whom CMA was performed. The minimum cut-off size for defining a homozygous stretch was 5 Mb. To focus on cases with no parental consanguinity, we further studied only patients in whom the total length of homozygous stretches did not exceed 28 Mb or 1% of the autosomal genome length. We identified 6 chromosomal regions where homozygous stretches appeared in at least 3 patients and excluded these from further analysis. In 2 out of 120 patients with an isolated finding of 1 or 2 non-recurrent LCSHs, a plausible candidate gene associated with their phenotype was identified within the homozygous stretch. In both of these cases, a pathogenic mutation was detected, leading to diagnoses of pyruvate kinase deficiency and Marinesco-Sjögren syndrome. To clarify whether previously found homozygous stretches could be important for the interpretation of genome-wide sequencing data, we report 7 cases in which homozygous stretches not encompassing a clinically associated gene were first found on CMA, followed by the diagnostic whole-exome sequencing. The diagnostic utility of single LCSHs, unlikely to be caused by uniparental disomy, is discussed in detail.

Multiple myeloma (MM) is preceded by monoclonal gammopathy of undetermined significance (MGUS). Up to date, it is difficult to predict an individual's time to disease progression and the treatment response. To examine whether the nuclear telomeric architecture will unravel some of these questions, we carried out. Three-dimensional (3D) telomere analysis on samples from patients diagnosed with MGUS and MM, as well as from patients who went into relapse. Telomere signal intensity, number of telomere aggregates, nuclear volume, and the overall nuclear telomere distribution (a/cratio) were analyzed. The telomeric profiles allowed for the differentiation of the disease stages. The telomeric profiles of myeloma cells obtained from blood and bone marrow aspirates were identical. Based on this study, we discuss the use of 3D telomere profiling as a potential future tool for risk stratification and personalized treatment decisions.

AbstractBackground:Females with a total or partial deletion of the short arm of the X chromosome have variable features of Turner syndrome, but mental retardation (MR) rarely occurs. The haploinsufficiency of deleted genes that escape X-inactivation may explain the occurrence of MR and autism. Ornithine transcarbamylase (OTC) deficiency is the most common urea cycle disorder and is inherited in an X-linked semi-dominant trait, and the OTCgene maps to Xp21. Methods:We report on a girl with MR, epilepsy and biochemical changes characteristic of OTC deficiency but no identifiable point mutation in the OTCgene. Standard G-banding cytogenetic analysis, whole genome karyotyping, and X-inactivation studies were performed to determine the genetic etiology of the OTC deficiency in the patient. Results:Cytogenetic analysis and molecular karyotyping using SNP array revealed a deletion of the whole short arm of the X chromosome (Xp22.33–p11.1). Inactivation studies also revealed a completely skewed X-inactivation. Conclusion:Our patient presented with MR, epilepsy, and some evidence of reduced OTC activity, but performed genetic studies gave no explanation for this phenotype. We hope that this case report contributes to the understanding of the underlying genetic factors of the manifestation of X-linked disorders in female patients.Copyright © 2011 S. Karger AG, Basel

A boy with signs of Klinefelter syndrome, mild facial dysmorphic features, and severely retarded speech development displayed a female karyotype with mosaicism for two marker chromosomes 48,XX,+mar1,+mar2[68]/47,XX,+mar1[19]/47,XX,+mar2[6]/46,XX[8]. Using chromosomal microdissection, locus‐specific fluorescence in situ hybridization (FISH), and PCR with several Y‐chromosome markers, the larger supernumerary marker chromosome (SMC) was characterized as a ring Y‐chromosome. Detection of the SRY‐region explained the male phenotype. The smaller second marker chromosome contained the pericentromeric region of chromosome 8. We suggest that the co‐occurrence of a partial Y‐chromosome and partial trisomy 8 explain the severe speech delay and the facial dysmorphic features. © 2006 Wiley‐Liss, Inc.

We report on a pure duplication of the proximal chromosome 2q in a 6.5‐year‐old boy with V‐shaped midline cleft palate and bifid uvula, posteriorly located tongue, and micrognathia (Pierre Robin sequence), celiac disease, failure to thrive, and developmental delay. Cytogenetic and FISH analysis indicated a duplication of chromosome 2q13‐q22. In general, pure proximal duplication or triplication of 2q is rare. The clinical features and chromosomal breakpoints of the 10 previously reported patients varied, and no common phenotype or proximal duplication/triplication 2q syndrome could be defined to date. However, based on four previous patients with different orofacial clefts and our case, a locus for orofacial clefting may be located at proximal 2q. The duplication/triplication comprised chromosome 2q13 in all five affected individuals including our patient. Our patient and three previous cases (two with cleft palate only (CPO) and one with cleft lip/palate (CL/P)) showed a cytogenetic breakpoint at 2q13, which could support the presence of a critical dominant gene disrupted by a common breakpoint, however, the fifth case with CPO showed different breakpoints, advocating against the disruption of a critical dominant gene and supporting that the overexpression of a gene(s) on chromosome 2q13‐q21 may cause cleft palate only (CPO) and Pierre Robin sequence. Hence, our findings support either the presence of one locus for orofacial clefting (CL/P, CPO, and Pierre Robin sequence) between markers D2S1897 (chromosome 2q12.2) and D2S2023 (chromosome 2q14.2), or alternatively the presence of a locus for CPO and Pierre Robin sequence on chromosome 2q13‐q21. © 2005 Wiley‐Liss, Inc.

Background: The study is a 12-year endoscopic follow-up investigation on the course of chronic gastritis and Helicobacter pylori infection in a sample of 81 Estonian people. Methods: The series is a subset from a random sample of 227 subjects in whom a gastroduodenal endoscopy had been done. The grade of superficial gastritis (SG), atrophy, and colonization of the mucosa by H. pylori was evaluated in biopsy specimens from both antrum and corpus in accordance with the principles of the Sydney System. Resufrs: The healing rate of the H. pylori and gastritis was 0.3% (3 of 81); H. pylori colonization with gastritis developed in 5 of 81 during the follow-up. The mean prevalence of atrophic gastritis (AG) was three times more common in the corpus than in the antrum on the average. The formation of new cases of AG and the disappearance of AG were quite equal during the follow-up, and the overall changes in the grade of SG and atrophy were slow. The mean life span of corpus AG was nearly three times as long as that of antrum AG. In the antrum the grade of chronic inflammation correlated positively with the grade of H. pylori colonization. In cases of SG a low grade of colonization of H. pylori in the antral mucosa in connection with moderate inflammation predicted a reduction or even a healing of gastritis in the long term. Conclusions: New H. pylori infections with subsequent gastritis may occur in adulthood; a healing of gastritis occurs but is a quite rare event in the course of the 12-year follow-up. Further, in the present random sample of Estonian people atrophic corpus gastritis did not show an overall progression, in contrast to our earlier findings.

The prevalence and density of Helicobacter pylori (HP) colonisation was assessed twice, with an interval of six years from antral and corpus biopsies from a randomly collected Estonian urban population sample. Positive HP colonisation was found in either at 1st or 2nd or in both examinations in 85 out of 86 subjects in whom gastritis without atrophy (chronic inflammation without atrophic changes, SG) either developed or remained during the follow-up at the SG level. There was a clear intraindividual tendency to keep the grade of HP colonisation at an unchanged level during the follow-up: the hypothesis of random variation of HP colonisation during follow-up could be statistically rejected. Close to half of the subjects had at both examinations an identical grade of HP colonisation in the antral or corpus mucosa. Distinct changes in HP colonisation were observed in three instances: (1) the appearance of HP colonisation occurred concomitantly with appearance of gastritis; (2) the development of antrum atrophic gastritis (AG) occurred with concomitant diminution and eventual disappearance of HP in the antral side, and (3) normalization of antral mucosa occurred with persistence of corpus AG with concomitant disappearance of HP colonisation at both sites of the stomach mucosa. The grade of HP colonisation increased with increase in severity of SG and decreased with the progression of AG changes. In the antrum at the SG level a distinct increase was seen both in the grade of HP colonisation and in the severity of SG up to middle age, but in the corpus mucosa only HP colonisation but no SG progression was seen in the younger age-groups. In the antrum, a life-long correlation was found between HP colonisation and inflammatory reaction. The efficiency of immune response against HP colonisation was calculated by using the ratio of SG score to grade of HP colonisation (IRR). The youngest age group (15-19 years at 1st examination) had a significantly higher immune response ratio (IRR) than other age groups. With regard to antral gastritis, those subjects whose SG regressed during the follow-up had a higher IRR than the other subjects. Parietal cell antibodies (PCA) developed in 2 subjects. Both the two subjects had positive HP colonisation at the 1st examination. In addition, one of them preserved HP positivity at the 2nd examination. These findings suggest that autoimmune mechanisms may start in subjects previously exposed to HP-related gastritis.

To study the prevalence and course of chronic gastritis (CG), 142 adult subjects collected at random from an Estonian urban area were endoscopically and bioptically examined at a six-year interval. The histology of the antral and corpus mucosae was evaluated by grading gastritis without ("superficial gastritis"; SG) and with atrophy ("atrophic gastritis"; AG) into mild, moderate and severe categories. A total of 135 (95%) and 139 (98%) subjects showed CG in the 1st and 2nd examinations, respectively. The CG healed in one subjects (0.7%), and in 5 out of 7 subjects with normal stomach in the 1st examination the CG started during the follow-up. No change in the severity of CG was seen in 24% of subjects with gastritis in the 1st examination. The main trend of CG was a slow, "one-step progression" in severity of inflammation and appearance of atrophy and intestinal metaplasia. Inflammation progressed significantly, especially in the young age groups and in the antrum in particular. The prevalence of AG increased linearly with age in corpus (mean annual risk 1.25%). Parietal cell antibodies (PCA) were found in 2 subjects in the 1st examination, and a further 2 subjects developed these antibodies later. Three of four PCA-positive subjects belonged to a subgroup of 8 elderly subjects who had corpus AG at both examinations and who also showed normal or normalizing mucosa in the antrum. It is concluded that CG is a slowly progressive disease advancing with time and, once started, rarely healing spontaneously.

The epidemiology and dynamics of gastritis were studied in a representative sample of an urban population of Estonia. The sample consisted of 227 subjects 15-69 years old who were examined by direct-vision endoscopic biopsy, and the data were subjected to dynamic evaluation by stochastic principles. The prevalence of antral gastritis (64) was similar to but that of body gastritis (62) higher than that in other population samples studied by us. Correspondingly, the prevalence of atrophic antral and body gastritis was high: 38 and 37, respectively. The prevalence of atrophic gastritis in the antrum and body increased significantly with age. On the other hand, no sex dependence of gastritis could be demonstrated. The prevalence of gastritis mainly affecting the body (32) was significantly higher in the present than in the other Estonian sample (19) studied by us. Complete loss of normal body glands was found in 14 subjects, and in 8 of these the antrum was normal or only slightly altered (type A gastritis). The prevalence of gastritis mainly affecting the body increased significantly with age, whereas that of gastritis mainly affecting the antrum decreased. Dynamic evaluation disclosed two basic dynamic patterns similar to those found in other population samples: the age-specific prevalences of gastritis increased with age according to the Poisson process, and gastritis started in the antrum at a younger age, but its progression was more rapid in the body mucosa. Dynamically, the chief finding of the sample was a markedly more rapid progression of the body gastritis than in other samples, which explains the high prevalence of gastritis mainly affecting the body mucosa (type A gastritis) in the present series.