A case of hepatitis-associated aplastic anaemia following living-donor liver transplantation for fulminant hepatitis showing loss of heterozygosity in the 6p chromosome in the affected liver.

The mechanisms underlying hepatitis-associated aplastic anaemia (HAAA) that occurs several weeks after the development of acute hepatitis are unknown. A 20-year-old male developed HAAA following living-donor liver transplantation for fulminant hepatitis. The patient's leucocytes lacked HLA-class I due to loss of heterozygosity in the short arm of chromosome 6p (6pLOH). Interestingly, the patient's liver cells resected during the transplantation also exhibited 6pLOH that affected the same HLA haplotype as the leucocytes, suggesting that CD8+ T cells recognizing antigens presented by specific HLA molecules on liver cells may have attacked the haematopoietic stem cells of the patient, leading to the HAAA development.

Survival-Related Genes on Chromosomes 6 and 17 in Medulloblastoma.

Survival of Medulloblastoma (MB) depends on various factors, including the gene expression profiles of MB tumor tissues. In this study, we identified 967 MB survival-related genes (SRGs) using a gene expression dataset and the Cox proportional hazards regression model. Notably, the SRGs were over-represented on chromosomes 6 and 17, known for the abnormalities monosomy 6 and isochromosome 17 in MB. The most significant SRG was HMGA1 (high mobility group AT-hook 1) on chromosome 6, which is a known oncogene and a histone H1 competitor. High expression of HMGA1 was associated with worse survival, primarily in the Group 3γ subtype. The high expression of HMGA1 was unrelated to any known somatic copy number alteration. Most SRGs on chromosome 17p were associated with low expression in Group 4ß, the MB subtype, with 93% deletion of 17p and 98% copy gain of 17q. GO enrichment analysis showed that both chromosomes 6 and 17 included SRGs related to telomere maintenance and provided a rationale for testing telomerase inhibitors in Group 3 MBs. We conclude that HMGA1, along with other SRGs on chromosomes 6 and 17, warrant further investigation as potential therapeutic targets in selected subgroups or subtypes of MB.

TERT promoter mutation and chromosome 6 loss define a high-risk subtype of ependymoma evolving from posterior fossa subependymoma.

Subependymomas are benign tumors characteristically encountered in the posterior fossa of adults that show distinct epigenetic profiles assigned to the molecular group "subependymoma, posterior fossa" (PFSE) of the recently established DNA methylation-based classification of central nervous system tumors. In contrast, most posterior fossa ependymomas exhibit a more aggressive biological behavior and are allocated to the molecular subgroups PFA or PFB. A subset of ependymomas shows epigenetic similarities with subependymomas, but the precise biology of these tumors and their potential relationships remain unknown. We therefore set out to characterize epigenetic traits, mutational profiles, and clinical outcomes of 50 posterior fossa ependymal tumors of the PFSE group. On histo-morphology, these tumors comprised 12 ependymomas, 14 subependymomas and 24 tumors with mixed ependymoma-subependymoma morphology. Mixed ependymoma-subependymoma tumors varied in their extent of ependymoma differentiation (2-95%) but consistently exhibited global epigenetic profiles of the PFSE group. Selective methylome analysis of microdissected tumor components revealed CpG signatures in mixed tumors that coalesce with their pure counterparts. Loss of chr6 (20/50 cases), as well as TERT mutations (21/50 cases), were frequent events enriched in tumors with pure ependymoma morphology (p < 0.001) and confined to areas with ependymoma differentiation in mixed tumors. Clinically, pure ependymoma phenotype, chr6 loss, and TERT mutations were associated with shorter progression-free survival (each p < 0.001). In conclusion, our results suggest that subependymomas may acquire genetic and epigenetic changes throughout tumor evolution giving rise to subclones with ependymoma morphology (resulting in mixed tumors) that eventually overpopulate the subependymoma component (pure PFSE ependymomas).

Chromosome 6p SNP microhaplotypes and IgG3 levels in hemochromatosis probands with HFE p.C282Y homozygosity.

Subnormal IgG1 or IgG3 levels occurred in 30% of hemochromatosis probands with HFE p.C282Y homozygosity and were concordant in HLA-identical siblings. We sought to identify factors associated with IgG subclasses in Alabama probands with p.C282Y homozygosity evaluated for 500 kb microhaplotypes AAT and GGG defined by SNPs in chromosome 6p genes PGBD1, ZNF193, and ZNF165. In regressions on IgG subclasses, we used: age; sex; GGG (dichotomous); iron removed to achieve depletion; CD8+ T-lymphocytes; and other IgG subclasses. Among 49 probands, AAT and GGG occurred in 95.9% and 16.3%, respectively. Thirteen probands (26.5%) had subnormal IgG1; 11 probands (22.4%) had subnormal IgG3. Mean IgG3 was higher in probands with than without GGG (75 mg/dL [95% confidence interval 63, 89] vs. 58 mg/dL [49, 71], respectively; p = 0.0321). Regression on IgG3 revealed: GGG positivity (p = 0.0106); and IgG1 (p = 0.0015). In a replication cohort of 22 Portugal probands with p.C282Y homozygosity, mean IgG3 was higher in probands with than without GGG (46 ±â€¯16 vs. 31 ±â€¯12 mg/dL, respectively; p = 0.0410). We conclude that mean IgG3 levels are higher in hemochromatosis probands with p.C282Y homozygosity with chromosome 6p microhaplotype GGG than in probands homozygous for microhaplotype AAT.

Novel Phenotype of 6p25 Deletion Syndrome Presenting Juvenile Parkinsonism and Brain Calcification.

BACKGROUND: Chromosome 6p25 deletion syndrome is a rare neurocristopathy with variable clinical features. The objective of the current study was to describe a novel phenotype for autosomal-dominant chromosome 6p25 deletion syndrome. The presentation included bilateral basal ganglia and subcortical calcifications and juvenile parkinsonism, resembling primary familial brain calcification. METHODS: Phenotypic characterization, exome sequencing, and oligonucleotide array were carried out in the index family. RESULTS: The index patient and her mother had a history of developmental delay, mild facial dysmorphism, Axenfield eye anomalies, slight intellectual disability, and subsequently developed levodopa-responsive parkinsonism in early adulthood. Brain-computed tomography showed bilateral basal ganglia and subcortical calcifications. Magnetic resonance imaging revealed diffuse white matter lesions. A 99mTc TRODAT single-photon emission computed tomography scan revealed bilateral dopaminergic denervation. Whole-exome sequencing and oligonucleotide array-based comparative genomic hybridization revealed a 2.27-Mb chromosome 6pter-p24 deletion, which cosegregated within the family. CONCLUSIONS: Our findings extended the current phenotypic spectrum of chromosome 6p25 deletion syndrome. © 2020 International Parkinson and Movement Disorder Society.

Human leukocyte antigen association with familial steroid-sensitive nephrotic syndrome.

Steroid-sensitive nephrotic syndrome (SSNS) is the most common form of nephrotic syndrome in childhood. Cases with the familial occurrence of SSNS suggest that genetics may play a role in the disease. Human leucocyte antigen (HLA) alleles have been associated with SSNS. We present genetic findings in nine families (44 participants), each with at least two affected siblings. A total of 19 patients were affected with familial SSNS. Six of nine families showed linkage to markers on chromosome 6p (27.29-33.97 Mbp) (Hg19), especially to markers D6S1629 and D6S1560 on HLA dense region in this location. Interestingly, we also found linkage of disease phenotype of familial SSNS on chromosome 15 (91.7-96.9 Mbp) (Hg19) with a logarithm of odds (LOD) score Z = 3.02.Conclusion: Our findings confirm the linkage of HLA markers on chromosome 6, which strengthens the association of HLA alleles in SSNS. What is Known: • Human leukocyte antigen (HLA) alleles have been associated with idiopathic steroid-sensitive nephrotic syndrome (SSNS). Only few studies have investigated the association between HLA alleles and familial SSNS. What is New: • We present evidence of linkage of familial SSNS to chromosome 6p (27.29-33.97 Mbp) (Hg19), especially to markers D6S1629 and D6S1560 on HLA dense region in this location. We also found linkage of the disease phenotype of familial SSNS on chromosome 15 (91.7-96.9 Mbp) (Hg19) with a logarithm of odds (LOD) score of Z = 3.02 following autosomal recessive inheritance pattern.

A paternal t(6;22)(q25.3;p12) leading to a deleted and satellited der(6) in a short-lived infant.

BACKGROUND: Non-acrocentric satellited chromosomes mostly result from familial balanced insertions or translocations with p12 or p13 of any acrocentric. Although all non-acrocentrics have been involved, only 12 instances of chromosome 6 involvement are known. CASE PRESENTATION: A female infant exhibited clinical features typical of 6qter deletions and also generalized hypertrichosis and synophrys, traits seldom reported in patients with similar imbalances or haploinsufficiency of ARID1B located in 6q25.3. She had a paternal derivative satellited 6q of a t(6;22)(q25.3;p12)pat entailing a 6q terminal deletion, karyotype 46,XX,der(6)t(6;22)(q25.3;p12)pat [16].ish del 6q subtel-. CONCLUSION: Male and female carriers of reciprocal translocations or insertions between chromosome 6 and the short arm of any acrocentric have few unbalanced offspring mostly by adjacent-1 segregation. In addition, spontaneous abortions or male infertility was present in 7/13 instances of satellited chromosome 6.

[Waldenström macroglobulinemia: Japanese perception].

Waldenström macroglobulinemia (WM) is a rare low-grade B-cell lymphoma. This report focuses on WM in Japan. Regarding epidemiology, per the 2016 registry data by the Japanese Society of Hematology, WM and lymphoplasmacytic lymphoma (LPL) cases were 229 and 125, respectively (1.97% of 17,957 mature lymphoid malignancies), with the annual incidence of WM/LPL in Japan 2.8 per million. In addition, 6q deletion (6q del) is the leading aberration and one of the poor prognostic factors in WM. Our findings suggested that the serum IgM level was higher in WM with 6q del compared with those without, and the B-cell receptor signaling pathway and IL-21 receptor expression were activated in WM with 6q del. Hence, these findings might be attributed to the aggressiveness of the WM with 6q del. Regarding treatment, recent studies investigating the epidemiological treatment pattern for WM have reported rituximab (R) monotherapy and alkylating regimen (±R) as the leading initial treatment. Nevertheless, ideal treatment algorithm in Japan warrants further investigation.

Gray Matter Heterotopia, Mental Retardation, Developmental Delay, Microcephaly, and Facial Dysmorphisms in a Boy with Ring Chromosome 6: A 10-Year Follow-Up and Literature Review.

Ring chromosome 6, r(6), is an extremely rare cytogenetic abnormality with clinical heterogeneity which arises typically de novo. The phenotypes of r(6) can be highly variable, ranging from almost normal to severe malformations and neurological defects. Up to now, only 33 cases have been reported in the literature. In this 10-year follow-up study, we report a case presenting distinctive facial features, severe developmental delay, and gray matter heterotopia with r(6) and terminal deletions of 6p25.3 (115426-384174, 268 kb) and 6q26-27 (168697778-170732033, 2.03 Mb) encompassing 2 and 15 candidate genes, respectively, which were detected using G-banding karyotyping, FISH, and chromosomal microarray analysis. We also analyzed the available information on the clinical features of the reported r(6) cases in order to provide more valuable information on genotype-phenotype correlations. To the best of our knowledge, this is the first report of gray matter heterotopia manifested in a patient with r(6) in China, and the deletions of 6p and 6q in our case are the smallest with the precise size of euchromatic material loss currently known.

Successful off-label sulfonylurea treatment of neonatal diabetes mellitus due to chromosome 6 abnormalities.

Chromosome 6 abnormalities such as paternal uniparental isodisomy, paternal 6q24 duplication, and maternal DMR (differentially methylated region) hypomethylation are a common cause of transient neonatal diabetes mellitus (TNDM). Oral sulfonylurea (SU) is used off-label to treat permanent neonatal diabetes mellitus owing to potassium channel mutation but has not been evaluated in TNDM. Our objective was to evaluate the efficacy and safety of SU therapy in chromosome 6-related TNDM. Description of 3 case reports and literature review was the subject of the study. SU therapy was successful in 2 patients (initiated during neonatal life in 1 patient and during relapse in the other) but failed in the other despite the use of high dosage. The literature review identified 11 cases of patients with chromosome 6-related TNDM treated with SU, including 4 treated before remission and 7 after the relapse. SU therapy was consistently effective, although 4 patients treated after the relapse required multiple oral medications. None of the patients needed associated insulin therapy. No side effects of SU or complications of diabetes were reported. SU seems effective and safe in chromosome 6-related TNDM treatment when used to treat the initial episode of diabetes or the relapse. It improves patients' and families' quality of life. SU is available only as oral tablets. A pediatric dosage form would facilitate the treatment of neonates and infants.

Investigation of major genetic alterations in neuroblastoma.

Neuroblastoma (NB) is the most common extracranial solid tumor in childhood. This malignancy shows a wide spectrum of clinical outcome and its prognosis is conditioned by manifold biological and genetic factors. We investigated the tumor genetic profile and clinical data of 29 patients with NB by multiplex ligation-dependent probe amplification (MLPA) to assess therapeutic risk. In 18 of these tumors, MYCN status was assessed by fluorescence in situ hybridization (FISH). Copy number variation was also determined for confirming MLPA findings in two 6p loci. We found 2p, 7q and 17q gains, and 1p and 11q losses as the most frequent chromosome alterations in this cohort. FISH confirmed all cases of MYCN amplification detected by MLPA. In view of unexpected 6p imbalance, copy number variation of two 6p loci was assessed for validating MLPA findings. Based on clinical data and genetic profiles, patients were stratified in pretreatment risk groups according to international consensus. MLPA proved to be effective for detecting multiple genetic alterations in all chromosome regions as requested by the International Neuroblastoma Risk Group (INRG) for therapeutic stratification. Moreover, this technique proved to be cost effective, reliable, only requiring standard PCR equipment, and attractive for routine analysis. However, the observed 6p imbalances made PKHD1 and DCDC2 inadequate for control loci. This must be considered when designing commercial MLPA kits for NB. Finally, four patients showed a normal MLPA profile, suggesting that NB might have a more complex genetic pattern than the one assessed by presently available MLPA kits.

Endocrine mucin-producing sweat gland carcinoma: A study of 11 cases with molecular analysis.

BACKGROUND: Endocrine mucin-producing sweat gland carcinoma (EMPSGC) is a rare, low-grade adnexal neoplasm that most commonly involves the eyelid. Analogous to solid papillary carcinoma of the breast, it probably represents a precursor lesion to mucinous carcinoma. Here, we describe 11 cases of EMPSGC with molecular analysis. METHODS: We performed a retrospective search of the Johns Hopkins Medical Institute pathology database and identified 11 cases of EMPSGC. Immunohistochemistry was performed for chromogranin, synaptophysin, neuron specific enolase, estrogen receptor (ER), epithelial membrane antigen (EMA), cytokeratin 7 (CK7), and cytokeratin 20 (CK20). Array comparative genomic hybridization (aCGH) and BRAFV600E pyrosequencing were performed on two and three cases, respectively. RESULTS: We observed a strong female predilection (73% females, 8/11 cases) with an average age of 66 years (range, 56-83 years). EMPSGCs were associated with adjacent benign sweat gland cysts (3/11), atypical intraductal proliferation (1/11), and mucinous carcinoma (1/11). Immunohistochemically, all tumors expressed at least one neuroendocrine marker, ER, EMA, and CK7, and were negative for CK20. aCGH demonstrated a 6p11.2 to 6q16.1 deletion (1/2 cases). All cases were negative for BRAFV600E mutation (3/3 cases). CONCLUSION: This series provides further histopathologic support that EMPSGC represents a multistage progression to mucinous carcinoma. Additional studies are needed to understand its molecular mechanisms.

Maternal uniparental disomy for chromosome 6 in a patient with IUGR, ambiguous genitalia, and persistent mullerian structures.

Maternal uniparental disomy of chromosome 6 [upd(6)mat] is rare and has only been previously reported 13 times with the main associated phenotype being IUGR. We present a case of a male patient with isodisomy upd(6)mat resulting in severe IUGR and ambiguous genitalia, a phenotype not previously described in association with this chromosome finding. The patient initially presented prenatally with IUGR at 19 weeks gestation with placental dysfunction and ambiguous genitalia noted at 27 weeks. Postnatally, the patient had external genital abnormalities, the gonads were in the inguinal canal and there was a rudimentary appearing vagina and uterus. Karyotype is 46, XY and SNP array revealed maternal isodisomy of 171 Mb at 6p25.3q27 with no pathogenic copy number variants. To our best knowledge, this is the first case of an XY patient with upd(6)mat with IUGR and ambiguous genitalia, further supporting previous reports regarding an association between upd(6)mat and IUGR. This patient also presented with a disorder of sex development (46, XY DSD) with the sex chromosome being male and positive for the SRY gene, testicular gonadal sex and abnormal external and internal genitalia. © 2016 Wiley Periodicals, Inc.

Cytological and molecular analysis of wheat - Agropyron cristatum translocation lines with 6P chromosome fragments conferring superior agronomic traits in common wheat.

Agropyron cristatum (2n = 4x = 28, PPPP) is a wild relative of common wheat and confers several desirable agronomic traits to wheat, such as high grain number per spike and enhanced resistance to certain diseases. Development of wheat - A. cristatum 6P translocation lines facilitates its utilization in wheat improvement. In this study, 26 wheat - A. cristatum 6P translocation lines were characterized by in situ hybridization (ISH) and 6P-specific sequence-tagged-site (STS) markers. These translocation lines carried different 6P chromosomal segments, which covered the whole 6P chromosome. FISH results showed that 15, 5, and 6 lines were translocated onto wheat A, B, and D genomes, respectively. Compared with the previous reports, a fine physical map of 6P chromosome was constructed, consisting of 31 chromosomal bins with 255 STS markers. Twelve translocation lines containing 6PS13∼14 chromosomal bins were highly resistant to leaf rust. Two lines showed high grain number per spike, and three lines displayed both enhanced grain number per spike and thousand-grain weight. Development of wheat - A. cristatum 6P translocation lines will not only provide novel wheat germplasm for wheat breeding but also be helpful to broaden the genetic basis of common wheat.

Glomerulopathy in patients with distal duplication of chromosome 6p.

BACKGROUND: Duplication of the distal part of chromosome 6p is a rare genetic syndrome. Renal involvement has been reported in the majority of patients, including a wide range of congenital abnormalities of kidney and urinary tract and, occasionally, a proteinuric glomerulopathy. CASE PRESENTATION: Here, we report a 13-year-old girl with 6p25.3p22.1 duplication who presented with proteinuria in infancy, was later diagnosed as focal segmental glomerulosclerosis, progressed to end-stage renal disease and was successfully transplanted. CONCLUSION: A systematic literature review suggests that 15-20 % of individuals with distal 6p duplication develop progressive proteinuric glomerulopathy. Monitoring of kidney function should be recommended in all cases.

[A case of partial 1p36.1 deletion and partial trisomy 6p diagnosed by karyotype]. / Un caso de deleción parcial 1p36.1 y trisomía parcial 6p diagnosticadas por cariotipo.

The deletion of chromosomal region 1p36 is one of the most common sub-telomeric microdeletion syndromes and has distinctive dysmorphic features. On the other hand, partial trisomy of the short arm of chromosome 6 is a rare chromosomal abnormality with a variable phenotype. OBJECTIVE: To report a case with both chromosome abnormalities, and to highlight the importance of the karyotype as a diagnostic tool in dysmorphology. CLINICAL CASE: The case of is presented of a two month-old infant with several craniofacial anomalies, neck haemangioma, sacral pit, rhizomelic shortening, small hands and feet, left unilateral cryptorchidism, and hypotonia. The infant also suffered intrauterine growth restriction and is the product of the eighth pregnancy of a 28 years old woman. Due to the unspecific findings in phenotype, a karyotype was requested, which showed a partial deletion of 1p36.1 and a partial trisomy of chromosome 6. CONCLUSION: The development of new techniques in molecular biology has improved diagnostic possibilities in medical genetics. However, the traditional karyotype remains as an important diagnostic tool in patients with multiple congenital anomalies.

Whole-genome profiling and shotgun sequencing delivers an anchored, gene-decorated, physical map assembly of bread wheat chromosome 6A.

Bread wheat (Triticum aestivum L.) is the most important staple food crop for 35% of the world's population. International efforts are underway to facilitate an increase in wheat production, of which the International Wheat Genome Sequencing Consortium (IWGSC) plays an important role. As part of this effort, we have developed a sequence-based physical map of wheat chromosome 6A using whole-genome profiling (WGP™). The bacterial artificial chromosome (BAC) contig assembly tools fingerprinted contig (fpc) and linear topological contig (ltc) were used and their contig assemblies were compared. A detailed investigation of the contigs structure revealed that ltc created a highly robust assembly compared with those formed by fpc. The ltc assemblies contained 1217 contigs for the short arm and 1113 contigs for the long arm, with an L50 of 1 Mb. To facilitate in silico anchoring, WGP™ tags underlying BAC contigs were extended by wheat and wheat progenitor genome sequence information. Sequence data were used for in silico anchoring against genetic markers with known sequences, of which almost 79% of the physical map could be anchored. Moreover, the assigned sequence information led to the 'decoration' of the respective physical map with 3359 anchored genes. Thus, this robust and genetically anchored physical map will serve as a framework for the sequencing of wheat chromosome 6A, and is of immediate use for map-based isolation of agronomically important genes/quantitative trait loci located on this chromosome.

A pure familial 6q15q21 split duplication associated with obesity and transmitted with partial reduction.

Familial transmission of chromosome 6 duplications is rare. We report on the first observation of a maternally-inherited pure segmental 6q duplication split into two segments, 6q15q16.3 and 6q16.3q21, and associated with obesity. Obesity has previously been correlated to chromosome 6 q-arm deletion but has not yet been assessed in duplications. The aim of this study was to characterize the structure of these intrachromosomal insertional translocations by classic cytogenetic banding, array-CGH, FISH, M-banding and genotyping using microsatellites and SNP array analysis, in a mother and four offspring. The duplicated 6q segments, 9.75 Mb (dup 1) and 7.05 Mb (dup 2) in size in the mother, were inserted distally into two distinct chromosome 6q regions. They were transmitted to four offspring. A son and a daughter inherited the two unbalanced insertions and displayed, like the mother, an abnormal phenotype with facial dysmorphism, intellectual disability, and morbid obesity. Curiously, two daughters with a normal phenotype inherited only the smaller segment, 6q16.3q21. The abnormal phenotype was associated with the larger proximal 6q15q16.3 duplication. We hypothesize a mechanism for this exceptional phenomenon of recurrent reduction and transmission of the duplication during meiosis in a family. We expect the interpretation of our findings to be useful for genetic counseling and for understanding the mechanisms underlying these large segmental 6q duplications and their evolution.

Juvenile myoclonic epilepsy and narcolepsy: A series of three cases.

OBJECTIVE: This paper sets out to demonstrate the coexistence of juvenile myoclonic epilepsy (JME) and narcolepsy that raises the possibility of a shared genetic predisposition to both conditions. METHODS: The electronic medical records (EMRs) were searched for narcolepsy and JME over 10years. RESULTS: We identified three young adult women diagnosed with JME in their teenage years, with myoclonic, generalized tonic-clonic, and absence seizure semiologies, along with psychiatric comorbidity, well managed on lamotrigine and/or levetiracetam. Our patients were also found to have disturbed sleep preceding the diagnosis of JME by many years, including excessive daytime sleepiness (EDS), fragmented nocturnal sleep, hypnagogic vivid hallucinations, and REM behavior disorder along with daytime cataplexy. They were ultimately diagnosed with coexisting narcolepsy, confirmed by sleep studies and multiple sleep latency testing, along with positive genetic testing for HLA-DQB1*0602 in all three patients. Stimulants, selective serotonin receptor inhibitors, and/or sodium oxybate were used to successfully treat their narcolepsy. SIGNIFICANCE: The coexistence of JME and narcolepsy has not been well recognized and may be clinically relevant. In addition, it raises the possibility of a shared genetic predisposition to both conditions.