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Spontaneous Chromosomal Instability in Peripheral Blood Lymphocytes

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Spontaneous Chromosomal Instability in Peripheral Blood Lymphocytes Genetics and Molecular Biology, 44, 3, e20200332 (2021) Copyright © Sociedade Brasileira de Genética. DOI: https://doi.org/10.1590/1678-4685-GMB-2020-0332 Short Communication Human and Medical Genetics Spontaneous chromosomal instability in peripheral blood lymphocytes from two molecularly confirmed Italian patients with Hereditary Fibrosis Poikiloderma: insights into cancer predisposition 1,2 2 2 2 3 Gaia Roversi *, Elisa Adele Colombo * , Ivana Magnani , Cristina Gervasini , Giuseppe Maggiore , Mauro Paradisi4# and Lidia Larizza5 1University of Milano-Bicocca, School of Medicine and Surgery, Department of Medicine and Surgery, Monza, Italy. 2Università degli Studi di Milano, Genetica Medica, Dipartimento di Scienze della Salute, Milan, Italy. 3Bambino Gesù Children’s Hospital IRCCS, Division of Hepatology and Gastroenterology, Rome, Italy. 4Istituto Dermopatico dell’Immacolata, IDI-IRCCS, Laboratory of Molecular and Cell Biology, Rome, Italy. 5IRCCS Istituto Auxologico Italiano, Laboratorio di Citogenetica e Genetica Molecolare Umana, Milan, Italy. Abstract Two Italian patients with the initial clinical diagnosis of Rothmund-Thomson syndrome were negative for RECQL4 mutations but showed in peripheral blood cells a spontaneous chromosomal instability significantly higher than controls. Revisiting after time their clinical phenotype, the suggestive matching with the autosomal dominant syndrome Poikiloderma, Hereditary Fibrosing with Tendon Contracture, Myopathy and Pulmonary fibrosis (POIKTMP) was confirmed by identification of the c.1879A>G (p.Arg627Gly) alteration in FAM111B. We compare the overall clinical signs of our patients with those of reported carriers of the same mutation and present the up-to-date mutational repertoire of FAM111B and the related phenotypic spectrum. Our snapshot highlights the age-dependent clinical expressivity of POIKTMP and the need to follow-up patients to monitor the multi-tissue impairment caused by FAM111B alterations. We link our chromosomal instability data to the role of FAM111B in cancer predisposition, pointed out by its implication in DNA-repair pathways and the outcome of pancreatic cancer in 2 out of 17 adult POIKTMP patients. The chromosomal instability herein highlighted well connects POIKTMP to cancer-predisposing syndromes, such as Rothmund-Thomson which represents the first hereditary poikiloderma entering in differential diagnosis with POIKTMP. Keywords: POIKTMP, FAM111B pathogenic variants, chromosomal instability, cancer predisposition, pancreatic carcinoma. Received: September 16, 2020; Accepted: April 08, 2021. Blood samples of two unrelated patients with a phenotype with ductopenia, as attested by hepatic biopsy, but had a much suggestive of a genodermatosis reminiscent of Rothmund- less impaired liver function; unfortunately, she prematurely Thomson syndrome (RTS, MIM #268400) were sent to our died following a trauma that occurred when she was 15 laboratory in 2002 to perform RECQL4 (MIM *603780) years old. Sanger sequencing of the entire RECQL4 gene molecular analysis, after obtainment of informed consents. (NG_016430.1), 21 exons and 20 introns, except for IVS12 Briefly, the two Italian patients, a male (patient A) and a minisatellite (Colombo et al., 2018), was carried out but did female (patient B) both representing the only child born to not detect any pathogenic alteration. non-consanguineous parents, presented typical RTS clinical In parallel to RECQL4 gene scan, spontaneous and signs, such as poikiloderma, sparse and rare hair, eyelashes induced chromosomal instability, a cellular hallmark of RTS and eyebrows, short stature, and photosensitivity, combined syndrome (Larizza et al., 2010) and other autosomal recessive with peculiar features, mainly oedema, muscular weakness syndromes driven by defects in RECQ helicase genes (such as and liver dysfunction with vanishing bile duct syndrome Werner Syndrome, MIM #277700) or entering in differential since infancy, rarely or never reported in RTS. Their clinical diagnosis with RTS (such as Fanconi Anemia, MIM Phenotypic conditions deteriorated with time and the liver involvement in Series-PS227650) was monitored on heparinized peripheral patient A caused ascites and sepsis that led him to premature blood lymphocytes from the two probands and six healthy death at age 17 years. Patient B also had a liver impairment: controls, including both probands’ parents. A minimum of 50 she suffered from idiopathic inflammatory cholangiopathy metaphase spreads prepared according to standard procedures and QFQ-banded were analysed per sample. As shown in Table 1, a significantly higher number of chromatid and Send correspondence to Elisa Adele Colombo. Università degli Studi di Milano, Genetica Medica, Dipartimento di Scienze della chromosome gaps and breaks per metaphase was highlighted Salute, via Antonio di Rudinì 8, 20142, Milan, Italy. E-mail: elisaadele. in both probands (patient A: 0.25 (13/52), patient B: 0.22 [email protected]. (11/51)) as compared to controls (0.11 (34/318)) (p<.05 at *These authors contributed equally to this work. the chi-square test). The chromosomal lesions, widespread in #In memoriam. the genome, involved different chromosomal locations, rarely 2 Roversi et al. coincident with fragile sites, as apparent in the set of eight The identified missense pathogenic variant affects different Q-banded chromosomes (Figure 1). Conversely, the a highly conserved amino acid residue placed in the loop search for chromosomal fragility after aphidicolin treatment that splits into two parts the functional enzymatic domain (0.4 M for 24 hr) did not evidence a rate of chromosome lesions of FAM111B (Mercier et al., 2013) (Figure 2B). Of note, significantly higher in the probands than in parallel control six additional FAM111B mutations map in this linker region lymphocytes cultures as the ratio of aberrations/metaphases (41 amino acids in length) that can be considered the major was 3.21 in patient A, 4.96 in patient B, and 4.52 in controls. mutation cluster; a minor cluster of three pathogenic variants As the molecular identity of the syndromic condition maps upstream the catalytic domain (Figure 2B). of the two patients was unknown at that time this data could Including our cases, the c.1879A>G (p.Arg627Gly) neither be associated with a specific rare syndrome nor mutation has been reported so far in five patients from four corroborated by testing similarly affected patients. families (Figure 2B and Table 2): our two from Italy, namely Many years later, the phenotype of our probands was patient A and patient B (alias F3-II1 reported by Mercier et revisited in the context of the literature. We noted a reasonable al., 2013, 2015), a third one from France (patient C, F1-II2, match between the phenotype of our cases and that of patients Mercier et al., 2013, 2015), and two from Algeria (patient D, with the ultra-rare autosomal dominant syndrome Poikiloderma, F2-II4, Mercier et al., 2013, 2015, 2019, and his son patient E, Hereditary Fibrosing, with Tendon contracture, Myopathy and F2-III1, Mercier et al., 2015). Table 2 summarizes the clinical Pulmonary fibrosis (POIKTMP, MIM #615704) (Khumalo signs of the reported POIKTMP cases sharing the hot spot et al., 2006; Mercier et al., 2013). Hence, targeted Sanger c.1879A>G (p.Arg627Gly) pathogenic variant. A detailed sequencing of the POIKTMP-causative gene FAM111B (MIM clinical report of patient B marking the evolution of the disease #615584), encoding a trypsin-like cysteine/serine peptidase can be found in Supplementary File 1. (Mercier et al., 2013), highlighted on both our patients the Briefly, all patients showed in the first year of life monoallelic c.1879A>G alteration (NG_034129.1) (Figure poikiloderma, predominant in the sun-exposed skin areas, 2A). This pathogenic variant is not present in the DNA of and hypotrichosis involving hair, eyelashes, and eyebrows. patient B’ mother, the only parent we could test. Moreover, Then, except patient E who was in the first childhood when we detected this alteration in the probands’ lymphoblastoid the disease is not yet fully expressed, all manifested muscle cell lines RNA (data not shown) confirming the stability of weakness and limb contractures starting from childhood the mutated FAM111B transcript r.1879A>G (p.Arg627Gly). and/or adolescence. Patient C (F1-II2) suffered from asthma Table 1 – Spontaneous chromosomal instability in peripheral blood cells from two unrelated patients with a Rothmund-Thomson-like phenotype. Patients Controls Observed aberrations Parents of patient A Parents of patient B Patient A Patient B Controls total Control 1 Control 2 Mother Father Mother Father Chromatid Gaps 7 4 19 1 2 5 3 5 3 Chromatid Breaks 1 0 5 1 0 3 0 0 1 Chromosome Gaps 1 4 6 1 0 2 0 2 1 Chromosome Breaks 4 3 4 1 1 1 1 0 0 Total aberrations 13 11 34 4 3 11 4 7 5 No. scored metaphases 52 51 318 50 54 53 56 54 51 Aberrations/ metaphase 0.25* 0.22* 0.11* 0.08 0.06 0.21 0.07 0.13 0.10 * Significant at p < .05 at the chi-square test Figure 1 – Spontaneous breaks and gaps in two unrelated Italian patients with a clinical presentation reminiscent of Rothmund-Thomson syndrome. Selected representative images document the spontaneous breaks and gaps observed in the QFQ-banded chromosome spreads from blood samples of the two patients herein reported. Chromosomal instability in POIKTMP 3 Figure 2 – The mutational repertoire of FAM111B. A) Electropherograms showing the c.1879A>G FAM111B missense variant (framed by the red rectangle) detected in
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