Mosaic Variegated Aneuploidy syndrome 2 caused by biallelic variants in CEP57, two new cases and review of the phenotype

Santos‐Simarro, Fernando; Pacio‐Míguez, Marta; Cueto‐González, Anna M.; Mansilla, Elena; Valenzuela, Irene; López-Grondona, Fermina; Lledín, María D.; Schüffelmann, Cristina; Pozo, Ángela del; Solís, Mario; Vallcorba, Patricia; Lapunzina, Pablo; Suso, Juan José Menéndez; Siccha, Sofía M; Montejo, Juan Manuel; Mena, Rocío; Jiménez-Rodríguez, Carmen; García‐Miñaúr, Sixto; Palomares‐Bralo, María

doi:10.1016/j.ejmg.2021.104338

Cited by 8 publications

(11 citation statements)

References 18 publications

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“…All 12 patients from the literature exhibited a severe postnatal growth retardation, most of them had facial dysmorphisms including triangular face, prominent forehead, micrognathia, and small, low-set ears. While congenital heart defects and vascular malformations are relatively common in patient with CEP57 [Santos-Simarro et al, 2021], patient II-7 did not exhibit anomalies of the heart. In mouse models, CEP57 has been identified as a haploinsufficiency tumor suppressor [Aziz et al, 2018], but tumors have not yet been reported in MVA2 patients with CEP57 variants.…”

Section: Discussionmentioning

confidence: 80%

“…In mouse models, CEP57 has been identified as a haploinsufficiency tumor suppressor [Aziz et al, 2018], but tumors have not yet been reported in MVA2 patients with CEP57 variants. However, an increased tumor risk cannot be ruled out in CEP57-associated MVA2 due to the small number of cases [Dery et al, 2020;Santos-Simarro et al, 2021].…”

Section: Discussionmentioning

confidence: 99%

“…Up to now, only 4 different variants in CEP57 have been reported in patients with MVA2 in the literature [Santos-Simarro et al, 2021]. The majority of patients with MVA2 (8 out of 12) presented a homozygous 11-bp insertion in exon 9 (NM_014679.4: c.915_925dup11).…”

Section: Discussionmentioning

confidence: 99%

“…MVA is caused by autosomal recessive pathogenic variants in 3 different genes, BUB1B (MVA1 [OMIM 257300]), CEP57 (MVA2 [OMIM 614114]), and TRIP13 (MVA3 [OMIM 617598]) [Hanks et al, 2004;Snape et al, 2011;Yost et al, 2017]. Clinical features comprise intrauterine growth retardation (IUGR), postnatal short stature, rhizomelic shortening of upper and lower limbs, dysmorphic features, microcephaly, and normal or mildly delayed development [for review, see Santos-Simarro et al, 2021] (Table 1). Additionally, tumor predisposition is reported for MVA patients carrying variants in BUB1B and TRIP13, whereas for CEP57 this association has not yet been reported [Dery et al, 2020].…”

Section: Introductionmentioning

confidence: 99%

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Mosaic Variegated Aneuploidy Syndrome and Noonan Syndrome in the Same Family

et al. 2022

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Introduction: Mosaic variegated aneuploidy syndrome 2 (MVA2) and Noonan syndrome (NS) are 2 genetic disorders with overlapping clinical features, including intrauterine growth retardation, dysmorphic features, and heart defects. Whereas NS is a well-known congenital entity, MVA2 is rare, and only a few cases have been reported in the literature. Case Presentation: We report on the molecular findings in 3 patients with short stature phenotypes from the same family. By considering the clinical overlap between the patients, a common cause for the small stature was assumed in the beginning, but by whole exome analysis (WES) it turned out that the phenotypes were caused by different pathogenic variants in CEP57 and PTPN11, respectively. As a result, both MVA2 and NS occurred in the same family. Conclusion: As our example shows, the parallel occurrence of pathogenic alterations in different genes in the same family constitutes a challenge for the interpretation of WES data and has to be considered. The diagnostic workup illustrates the need for a careful anamnesis and molecular documentation in affected and healthy family members. The knowledge on the different molecular causes underlying the features of the affected family members is the basis for personalised therapeutic managements and can avoid unnecessary burden and even contraindicated therapies; while in patients with NS carrying PTPN11 variants growth hormone treatment leads to height increase, patients with MVA2 carrying CEP57 probably do not benefit from it.

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Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mosaic Variegated Aneuploidy Syndrome and Noonan Syndrome in the Same Family

et al. 2022

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“…Based on our review of 14 articles retrieved from PubMed, 12 cases of MVA2 caused by CEP57 variants are summarized in Supplementary Table S1 . These cases were identified in Mexico, the Caucasus, Morocco, and Pakistan (Santos‐Simarro et al, 2021 ). To date, four CEP57 variants have been reported to cause MVA2.…”

Section: Discussionmentioning

confidence: 99%

A novel CEP57 variant associated with mosaic variegated aneuploidy syndrome in a Chinese female presenting with short stature, microcephaly, brachydactyly, and small teeth

Feng

Chang

Zhang

et al. 2022

Molec Gen & Gen Med

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Background: Mosaic variegated aneuploidy (MVA) syndrome is a rare, autosomal recessive genetic disease. Here, we report an ultra-rare case of MVA syndrome associated with a CEP57 variant. Methods:We retrospectively analyzed the clinical data of a 9-year-old female patient and surveyed her family members. Whole-exome sequencing and karyotype analysis were performed; suspected mutations were verified using Sanger sequencing. Results:The patient presented with intrauterine growth restriction, short stature, microcephaly, facial dysmorphism, brachydactyly, and small teeth, and she showed unsatisfactory response to GH replacement therapy. Laboratory tests revealed high insulin-like growth factor-1 levels. Karyotype analysis of the peripheral blood showed mosaic variegated aneuploidies. Whole-exome and Sanger sequencing revealed a novel homozygous nonsense variant, NM_014679.4: c.312 T > G, in CEP57 that leads to translation termination (p.Tyr104*). The parents were heterozygous carriers of the identified variant. Conclusion:This study presents an ultra-rare case of CEP57-driven MVA syndrome, identifying a novel homozygous nonsense variant of CEP57 (p.Tyr104*).Our findings enrich the CEP57 mutational spectrum and emphasize the importance of genetic testing in patients with microcephaly and short stature. Furthermore, we conclude that growth hormone treatment is ineffective in such patients.

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A Distinctive Type of Mosaic Variegated Aneuploidy: Case Report and Review of the Literature

Frattini,

Micheloni,

Musio

et al. 2024

American J of Med Genetics Pt A

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Mosaic variegated aneuploidy (MVA) is an autosomal recessive disorder characterized by mosaic aneuploidies, predominantly trisomies, involving multiple different chromosomes and tissues. The proportion of aneuploid cells varies, and most patients present with intrauterine growth delay, microcephaly, and a broad spectrum of congenital abnormalities. We report a patient with a distinctive type of MVA discovered in bone marrow (BM) when she was 3‐month‐old due to neutropenia and hypocellular bone marrow. She was followed up for more than 20 years, and different trisomic cells were repeatedly discovered in different tissues, whereas her clinical picture has never been severe. The main sign remained intermittent neutropenia, not cyclic and often not too severe, occasionally with anemia and thrombocytopenia. Retromicrognathia was the only dysmorphic sign. Unlike other patients with MVA, the trisomies in all tissues involved almost invariably chromosomes 18 and 19. Therefore, the peculiarities of our patient were the clinical and the atypical cytogenetic pictures. Nevertheless, we looked for mutations in the seven causative genes of the known types of MVA, but the results were negative. Then, we analyzed the entire exome to find out other possible causing mutations, but also this attempt failed to discover a possible cause of this distinctive form of MVA.

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Mosaic Variegated Aneuploidy syndrome 2 caused by biallelic variants in CEP57, two new cases and review of the phenotype

Cited by 8 publications

References 18 publications

Mosaic Variegated Aneuploidy Syndrome and Noonan Syndrome in the Same Family

Mosaic Variegated Aneuploidy Syndrome and Noonan Syndrome in the Same Family

A novel CEP57 variant associated with mosaic variegated aneuploidy syndrome in a Chinese female presenting with short stature, microcephaly, brachydactyly, and small teeth

A Distinctive Type of Mosaic Variegated Aneuploidy: Case Report and Review of the Literature

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