Cytogenomic and phenotypic analysis in low‐level monosomy 7 mosaicism with non‐supernumerary ring chromosome 7

Salas-Labadía, Consuelo; Cervantes-Barragán, David E.; Cruz-Alcívar, Roberto; Daber, Robert; Conlin, Laura K.; Leonard, Laura D.; Spinner, Nancy B.; Durán‐McKinster, Carola; Montellano, David José Dávila-Ortiz de; Castillo-Ruiz, V. Del; Pérez-Vera, Patricia

doi:10.1002/ajmg.a.36503

Cited by 8 publications

(9 citation statements)

References 26 publications

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“…Analysis by SNP array showed a 0.8 Mb deletion in 7p22.3 (involving eight genes) and a 7.5 Mb deletion in 7q36 (involving 29 genes including some involved in genital and central nervous system development). As shown in Table 2, most of the deleted genes were involved in CNS, urogenital and M-S systems alterations associated with some of the clinical manifestations of the patient (Table 2) [21]. 2) Cytogenetic analysis identified three cell lines in different proportions in patient PM25: One with supernumerary marker chromosome, another with trisomy 14, and a normal cell line.…”

Section: Resultsmentioning

confidence: 99%

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Genetic and clinical characterization of 73 Pigmentary Mosaicism patients: revealing the genetic basis of clinical manifestations

Salas-Labadía

Gómez-Carmona

Cruz-Alcívar

et al. 2019

Orphanet J Rare Dis

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BackgroundPigmentary mosaicism constitutes a heterogeneous group of skin pigmentation alterations associated with multisystem involvement. The aim of this study was to establish a complete cytogenetic and molecular characterization of PM patients, emphasizing on searching for possible low chromosomal mosaicism and on establishing an accurate genotype-phenotype correlation.ResultsA total of 73 patients were included (3 months to 18 years of age), 52% male and 48% female. Observed in 69 (95%) patients, the most frequent pattern of pigmentation was fine and whorled BL, which was associated with disseminated skin extent in 41 (59%) patients. Central nervous system (84%) alterations were the most frequent observed in the group of patients, followed by the musculoskeletal (53%) and ophthalmologic (27%) alterations. Considering the pattern of pigmentation, no significant differences in association with skin extent or extracutaneous manifestations were detected. Following a strict cytogenetic analysis strategy, screening metaphases from three different tissues (peripheral blood, hyperpigmented and hypopigmented skin) we found that 23/73 patients had chromosomal abnormalities classified as follows: 1) Mosaic with 2 or more different cell lines with structural alterations n = 19; 2) Polyploidy (mosaic) n = 1 and 3) Alterations in all cells in three different tissues n = 3. SNP array, array CGH and FISH were useful for the complete characterization of the chromosomal aberrations, for the detection of microdeletions in patients with normal karyotype but with strong clinical suspicious of chromosomal alteration, and for a better establishment of genotype-phenotype correlation. In 2 patients we found genes associated with some of the extracutaneous manifestations (SHH, MNX1, PPP2R2C).ConclusionsThis group of 73 patients finely described is the largest series of patients with pigmentary mosaicism reported worldwide. As we showed in this study, the followed analysis strategy allowed the detection of cytogenetic and molecular abnormalities, and made possible the establishment of genotype-phenotype associations in some patients. An important limitation of our study was the analysis of fibroblasts cultures instead of melanocytes and keratinocytes. In some cases the direct molecular DNA analysis of skin biopsy could be another choice.

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Section: Resultsmentioning

confidence: 99%

“…Loss of genomic regions was determined by decreases in the log R ratio. Mosaic proportions were estimated by B allele frequencies (BAF) [21, 22].…”

Section: Methodsmentioning

confidence: 99%

Genetic and clinical characterization of 73 Pigmentary Mosaicism patients: revealing the genetic basis of clinical manifestations

Salas-Labadía

Gómez-Carmona

Cruz-Alcívar

et al. 2019

Orphanet J Rare Dis

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“…However, there remain a number of areas in the genome where the genotype‐phenotype correlation is not well described. Isolated 7p22.3p22.2 deletions have been rarely described; most reported cases involve either a much larger region of the 7p arm (Schomig‐Spingler, Schmid, Brosi, & Grimm, ; Speleman, Craen, & Leroy, ) or have an additional copy number variation which is larger in size and believed to be the greater contributor to the individual's clinical presentation (Kohannim, Peredo, Dipple, & Quintero‐Rivera, ; Salas‐Labadia et al, ; Schmidt, Udink ten Cate, WeiB, & Kochler, ). To date, there have only been two reports describing individuals with pure monosomy 7p22.3p22.2.…”

Section: Introductionmentioning

confidence: 99%

Variable developmental delays and characteristic facial features—A novel 7p22.3p22.2 microdeletion syndrome?

Zambrano

Cristian

et al. 2017

American J of Med Genetics Pt A

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Isolated 7p22.3p22.2 deletions are rarely described with only two reports in the literature. Most other reported cases either involve a much larger region of the 7p arm or have an additional copy number variation. Here, we report five patients with overlapping microdeletions at 7p22.3p22.2. The patients presented with variable developmental delays, exhibiting relative weaknesses in expressive language skills and relative strengths in gross, and fine motor skills. The most consistent facial features seen in these patients included a broad nasal root, a prominent forehead a prominent glabella and arched eyebrows. Additional variable features amongst the patients included microcephaly, metopic ridging or craniosynostosis, cleft palate, cardiac defects, and mild hypotonia. Although the patients' deletions varied in size, there was a 0.47 Mb region of overlap which contained 7 OMIM genes: EIP3B, CHST12, LFNG, BRAT1, TTYH3, AMZ1, and GNA12. We propose that monosomy of this region represents a novel microdeletion syndrome. We recommend that individuals with 7p22.3p22.2 deletions should receive a developmental assessment and a thorough cardiac exam, with consideration of an echocardiogram, as part of their initial evaluation.

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“…Previous studies had demonstrated BRAF p.(V600E) mutations in single samples of CMN, with two reported cases of BRAF activation secondary to a chromosomal translocation involving 7q, demonstrated in melanocytes derived from the main CMN . Furthermore, multiple CMN is an established feature in patients with ring chromosome 7, with evidence of somatic mosaicism leading to significant gain of chromosome 7 within the CMN . However, a role for BRAF in CMN was debated, with no evidence for BRAF variants in true congenital naevi in one study .…”

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confidence: 99%

“…35 Furthermore, multiple CMN is an established feature in patients with ring chromosome 7, with evidence of somatic mosaicism leading to significant gain of chromosome 7 within the CMN. 42,43 However, a role for BRAF in CMN was debated, with no evidence for BRAF variants in true congenital naevi in one study. 27 A single case of multiple CMN where mutant BRAF was detected in more than one naevus from the same patient has now been published, 44 confirming clonality in that patient as opposed to a second hit, and effectively confirming the pathogenesis in previous reports of multiple CMN or CMN syndrome.…”

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confidence: 99%

Does the gene matter? Genotype–phenotype and genotype–outcome associations in congenital melanocytic naevi

et al. 2019

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Summary Background Genotype–phenotype studies can identify subgroups of patients with specific clinical features or differing outcomes, which can help shape management. Objectives To characterize the frequency of different causative genotypes in congenital melanocytic naevi (CMN), and to investigate genotype–phenotype and genotype–outcome associations. Methods We conducted a large cohort study in which we undertook MC1R genotyping from blood, and high‐sensitivity genotyping of NRAS and BRAF hotspots in 156 naevus biopsies from 134 patients with CMN [male 40%; multiple CMN 76%; projected adult size (PAS) > 20 cm, 59%]. Results Mosaic NRAS mutations were detected in 68%, mutually exclusive with BRAF mutations in 7%, with double wild‐type in 25%. Two separate naevi were sequenced in five of seven patients with BRAF mutations, confirming clonality. Five of seven patients with BRAF mutations had a dramatic multinodular phenotype, with characteristic histology distinct from classical proliferative nodules. NRAS mutation was the commonest in all sizes of CMN, but was particularly common in naevi with PAS > 60 cm, implying more tolerance to that mutation early in embryogenesis. Facial features were less common in double wild‐type patients. Importantly, the incidence of congenital neurological disease, and apparently of melanoma, was not altered by genotype; no cases of melanoma were seen in BRAF‐mutant multiple CMN, however, this genotype is rare. Conclusions CMN of all sizes are most commonly caused by mutations in NRAS. BRAF is confirmed as a much rarer cause of multiple CMN, and appears to be commonly associated with a multinodular phenotype. Genotype in this cohort was not associated with differences in incidence of neurological disease in childhood. However, genotyping should be undertaken in suspected melanoma, for guidance of treatment. What's already known about this topic? Multiple congenital melanocytic naevi (CMN) have been shown to be caused by NRAS mosaic mutations in 70–80% of cases, by BRAF mosaicism in one case report and by inference in some previous cases. There has been debate about genotypic association with different sizes of CMN, and no data on genotype–outcome. What does this study add? NRAS mosaicism was found in 68%, BRAF in 7% and double wild‐type in 25% of cases of CMN. NRAS was the commonest mutation in all sizes of CMN, but was nearly universal in projected adult size > 60 cm. BRAF is often associated with a distinct multinodular clinical/histological phenotype. Adverse outcomes did not differ between genotypes on current numbers.

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Cytogenomic and phenotypic analysis in low‐level monosomy 7 mosaicism with non‐supernumerary ring chromosome 7

Cited by 8 publications

References 26 publications

Genetic and clinical characterization of 73 Pigmentary Mosaicism patients: revealing the genetic basis of clinical manifestations

Genetic and clinical characterization of 73 Pigmentary Mosaicism patients: revealing the genetic basis of clinical manifestations

Variable developmental delays and characteristic facial features—A novel 7p22.3p22.2 microdeletion syndrome?

Does the gene matter? Genotype–phenotype and genotype–outcome associations in congenital melanocytic naevi

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