DEBORA ROMEO BERTOLA
Projetos de Pesquisa
Unidades Organizacionais
Instituto da Criança, Hospital das Clínicas, Faculdade de Medicina - Médico
BIO, IB
LIM/36 - Laboratório de Pediatria Clínica, Hospital das Clínicas, Faculdade de Medicina
BIO, IB
LIM/36 - Laboratório de Pediatria Clínica, Hospital das Clínicas, Faculdade de Medicina
13 resultados
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- Cross-national harmonization of cognitive measures across HRS HCAP (USA) and LASI-DAD (India)(2022) VONK, Jet M. J.; GROSS, Alden L.; ZAMMIT, Andrea R.; BERTOLA, Laiss; AVILA, Justina F.; JUTTEN, Roos J.; GAYNOR, Leslie S.; SUEMOTO, Claudia K.; KOBAYASHI, Lindsay C.; O'CONNELL, Megan E.; ELUGBADEBO, Olufisayo; AMOFA, Priscilla A.; STAFFARONI, Adam M.; RENTERIA, Miguel Arce; TURNEY, Indira C.; JONES, Richard N.; MANLY, Jennifer J.; LEE, Jinkook; ZAHODNE, Laura B.Background As global populations age, cross-national comparisons of cognitive health and dementia risk are increasingly valuable. It remains unclear, however, whether country-level differences in cognitive function are attributable to population differences or bias due to incommensurate measurement. To demonstrate an effective method for cross-national comparison studies, we aimed to statistically harmonize measures of episodic memory and language function across two population-based cohorts of older adults in the United States (HRS HCAP) and India (LASI-DAD). Methods Data for 3,496 HRS HCAP (>= 65 years) and 3,152 LASI-DAD (>= 60 years) participants were statistically harmonized for episodic memory and language performance using confirmatory factor analysis (CFA) methods. Episodic memory and language factor variables were investigated for differential item functioning (DIF) and precision. Results CFA models estimating episodic memory and language domains based on a priori adjudication of comparable items fit the data well. DIF analyses revealed that four out of ten episodic memory items and five out of twelve language items measured the underlying construct comparably across samples. DIF-modified episodic memory and language factor scores showed comparable patterns of precision across the range of the latent trait for each sample. Conclusions Harmonization of cognitive measures will facilitate future investigation of cross-national differences in cognitive performance and differential effects of risk factors, policies, and treatments, reducing study-level measurement and administrative influences. As international aging studies become more widely available, advanced statistical methods such as those described in this study will become increasingly central to making universal generalizations and drawing valid conclusions about cognitive aging of the global population.
- Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome(2015) YAMAMOTO, Guilherme Lopes; AGUENA, Meire; GOS, Monika; HUNG, Christina; PILCH, Jacek; FAHIMINIYA, Somayyeh; ABRAMOWICZ, Anna; CRISTIAN, Ingrid; BUSCARILLI, Michelle; NASLAVSKY, Michel Satya; MALAQUIAS, Alexsandra C.; ZATZ, Mayana; BODAMER, Olaf; MAJEWSKI, Jacek; JORGE, Alexander A. L.; PEREIRA, Alexandre C.; KIM, Chong Ae; PASSOS-BUENO, Maria Rita; BERTOLA, Debora RomeoBackground Noonan syndrome is an autosomal dominant, multisystemic disorder caused by dysregulation of the RAS/mitogen activated protein kinase (MAPK) pathway. Heterozygous, pathogenic variants in 11 known genes account for approximately 80% of cases. The identification of novel genes associated with Noonan syndrome has become increasingly challenging, since they might be responsible for very small fractions of the cases. Methods A cohort of 50 Brazilian probands negative for pathogenic variants in the known genes associated with Noonan syndrome was tested through whole-exome sequencing along with the relatives in the familial cases. Families from the USA and Poland with mutations in the newly identified genes were included subsequently. Results We identified rare, segregating or de novo missense variants in SOS2 and LZTR1 in 4% and 8%, respectively, of the 50 Brazilian probands. SOS2 and LZTR1 variants were also found to segregate in one American and one Polish family. Notably, SOS2 variants were identified in patients with marked ectodermal involvement, similar to patients with SOS1 mutations. Conclusions We identified two novel genes, SOS2 and LZTR1, associated with Noonan syndrome, thereby expanding the molecular spectrum of RASopathies. Mutations in these genes are responsible for approximately 3% of all patients with Noonan syndrome. While SOS2 is a natural candidate, because of its homology with SOS1, the functional role of LZTR1 in the RAS/MAPK pathway is not known, and it could not have been identified without the large pedigrees. Additional functional studies are needed to elucidate the role of LZTR1 in RAS/MAPK signalling and in the pathogenesis of Noonan syndrome.
conferenceObject Novel mutations in fibronectin associated with metaphyseal fractures - Expanding the phenotype of patients with a subtype of spondylomethaphyseal dysplasia with ""corner fractures""(2018) ALM, Jessica J.; COSTANTINI, Alice; VALTA, Helena; BARATANG, Nissan Vida; YAP, Patrick; BERTOLA, Debora; YAMAMOTO, Guilherme; KIM, Chong A.; CHEN, Jiani; WIERENGA, Klaas J.; FANNING, Elizabeth A.; ESCOBAR, Luis; MCWALTER, Kirsty; MCLAUGHLIN, Heather; WILLAERT, Rebecca; BEGTRUP, Amber; REINHARDT, Dieter P.; MAKITIE, Outi; CAMPEAU, Philippe M.- Mutations in Fibronectin Cause a Subtype of Spondylometaphyseal Dysplasia with ""Corner Fractures''(2017) LEE, Chae Syng; FU, He; BARATANG, Nissan; ROUSSEAU, Justine; KUMRA, Heena; SUTTON, V. Reid; NICETA, Marcello; CIOLFI, Andrea; YAMAMOTO, Guilherme; BERTOLA, Debora; MARCELIS, Carlo L.; LUGTENBERG, Dorien; BARTULI, Andrea; KIM, Choel; HOOVER-FONG, Julie; SOBREIRA, Nara; PAULI, Richard; BACINO, Carlos; KRAKOW, Deborah; PARBOOSINGH, Jillian; YAP, Patrick; KARIMINEJAD, Ariana; MCDONALD, Marie T.; ARACENA, Mariana I.; LAUSCH, Ekkehart; UNGER, Sheila; SUPERTI-FURGA, Andrea; LU, James T.; COHN, Dan H.; TARTAGLIA, Marco; LEE, Brendan H.; REINHARDT, Dieter P.; CAMPEAU, Philippe M.Fibronectin is a master organizer of extracellular matrices (ECMs) and promotes the assembly of collagens, fibrillin-1, and other proteins. It is also known to play roles in skeletal tissues through its secretion by osteoblasts, chondrocytes, and mesenchymal cells. Spondylo-metaphyseal dysplasias (SMDs) comprise a diverse group of skeletal dysplasias and often manifest as short stature, growth-plate irregularities, and vertebral anomalies, such as scoliosis. By comparing the exomes of individuals with SMD with the radiographic appearance of ""corner fractures'' at metaphyses, we identified three individuals with fibronectin (FN1) variants affecting highly conserved residues. Furthermore, using matching tools and the SkelDys emailing list, we identified other individuals with de novo FN1 variants and a similar phenotype. The severe scoliosis in most individuals and rare developmental coxa vara distinguish individuals with FN1 mutations from those with classical Sutcliffe-type SMD. To study functional consequences of these FN1 mutations on the protein level, we introduced three disease-associated missense variants (p.Cys87Phe [c.260G>T], p.Tyr240Asp [c.718T>G], and p.Cys260Gly [c.778T>G]) into a recombinant secreted N-terminal 70 kDa fragment (rF70K) and the full-length fibronectin (rFN). The wild-type rF70K and rFN were secreted into the culture medium, whereas all mutant proteins were either not secreted or secreted at significantly lower amounts. Immunofluorescence analysis demonstrated increased intracellular retention of the mutant proteins. In summary, FN1 mutations that cause defective fibronectin secretion are found in SMD, and we thus provide additional evidence for a critical function of fibronectin in cartilage and bone.
- Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases(2015) VERLOES, Alain; DONATO, Nataliya Di; MASLIAH-PLANCHON, Julien; JONGMANS, Marjolijn; ABDUL-RAMAN, Omar A.; ALBRECHT, Beate; ALLANSON, Judith; BRUNNER, Han; BERTOLA, Debora; CHASSAING, Nicolas; DAVID, Albert; DEVRIENDT, Koen; EFTEKHARI, Pirayeh; DROUIN-GARRAUD, Valerie; FARAVELLI, Francesca; FAIVRE, Laurence; GIULIANO, Fabienne; ALMEIDA, Leina Guion; JUNCOS, Jorge; KEMPERS, Marlies; EKER, Hatice Kocak; LACOMBE, Didier; LIN, Angela; MANCINI, Grazia; MELIS, Daniela; LOURENCO, Charles Marques; SIU, Victoria Mok; MORIN, Gilles; NEZARATI, Marjan; NOWACZYK, Malgorzata J. M.; RAMER, Jeanette C.; OSIMANI, Sara; PHILIP, Nicole; PIERPONT, Mary Ella; PROCACCIO, Vincent; ROSELI, Zeichi-Seide; ROSSI, Massimiliano; RUSU, Cristina; SZNAJER, Yves; TEMPLIN, Ludivine; ULIANA, Vera; KLAUS, Mirjam; BON, Bregje Van; RAVENSWAAIJ, Conny Van; WAINER, Bruce; FRY, Andrew E.; RUMP, Andreas; HOISCHEN, Alexander; DRUNAT, Severine; RIVIERE, Jean-Baptiste; DOBYNS, William B.; PILZ, Daniela T.Baraitser-Winter, Fryns-Aftimos and cerebrofrontofacial syndrome types 1 and 3 have recently been associated with heterozygous gain-of-function mutations in one of the two ubiquitous cytoplasmic actin-encoding genes ACTB and ACTG1 that encode beta-and gamma-actins. We present detailed phenotypic descriptions and neuroimaging on 36 patients analyzed by our group and six cases from the literature with a molecularly proven actinopathy (9 ACTG1 and 33 ACTB). The major clinical anomalies are striking dysmorphic facial features with hypertelorism, broad nose with large tip and prominent root, congenital non-myopathic ptosis, ridged metopic suture and arched eyebrows. Iris or retinal coloboma is present in many cases, as is sensorineural deafness. Cleft lip and palate, hallux duplex, congenital heart defects and renal tract anomalies are seen in some cases. Microcephaly may develop with time. Nearly all patients with ACTG1 mutations, and around 60% of those with ACTB mutations have some degree of pachygyria with anteroposterior severity gradient, rarely lissencephaly or neuronal heterotopia. Reduction of shoulder girdle muscle bulk and progressive joint stiffness is common. Early muscular involvement, occasionally with congenital arthrogryposis, may be present. Progressive, severe dystonia was seen in one family. Intellectual disability and epilepsy are variable in severity and largely correlate with CNS anomalies. One patient developed acute lymphocytic leukemia, and another a cutaneous lymphoma, indicating that actinopathies may be cancer-predisposing disorders. Considering the multifaceted role of actins in cell physiology, we hypothesize that some clinical manifestations may be partially mutation specific. Baraitser-Winter cerebrofrontofacial syndrome is our suggested designation for this clinical entity.
- Genotype-Phenotype Correlation in NF1: Evidence for a More Severe Phenotype Associated with Missense Mutations Affecting NF1 Codons 844-848(2018) KOCZKOWSKA, Magdalena; CHEN, Yunjia; CALLENS, Tom; GOMES, Alicia; SHARP, Angela; JOHNSON, Sherrell; HSIAO, Meng-Chang; CHEN, Zhenbin; BALASUBRAMANIAN, Meena; BARNETT, Christopher P.; BECKER, Troy A.; BEN-SHACHAR, Shay; BERTOLA, Debora R.; BLAKELEY, Jaishri O.; BURKITT-WRIGHT, Emma M. M.; CALLAWAY, Alison; CRENSHAW, Melissa; CUNHA, Karin S.; CUNNINGHAM, Mitch; D'AGOSTINO, Maria D.; DAHAN, Karin; LUCA, Alessandro De; DESTREE, Anne; DHAMIJA, Radhika; EOLI, Marica; EVANS, D. Gareth R.; GALVIN-PARTON, Patricia; GEORGE-ABRAHAM, Jaya K.; GRIPP, Karen W.; GUEVARA-CAMPOS, Jose; HANCHARD, Neil A.; HERNANDEZ-CHICO, Concepcion; IMMKEN, LaDonna; JANSSENS, Sandra; JONES, Kristi J.; KEENA, Beth A.; KOCHHAR, Aaina; LIEBELT, Jan; MARTIR-NEGRON, Arelis; MAHONEY, Maurice J.; MAYSTADT, Isabelle; MCDOUGALL, Carey; MCENTAGART, Meriel; MENDELSOHN, Nancy; MILLER, David T.; MORTIER, Geert; MORTON, Jenny; PAPPAS, John; PLOTKIN, Scott R.; POND, Dinel; ROSENBAUM, Kenneth; RUBIN, Karol; RUSSELL, Laura; RUTLEDGE, Lane S.; SALETTI, Veronica; SCHONBERG, Rhonda; SCHREIBER, Allison; SEIDEL, Meredith; SIQVELAND, Elizabeth; STOCKTON, David W.; TREVISSON, Eva; ULLRICH, Nicole J.; UPADHYAYA, Meena; MINKELEN, Rick van; VERHELST, Helene; WALLACE, Margaret R.; YAP, Yoon-Sim; ZACKAI, Elaine; ZONANA, Jonathan; ZURCHER, Vickie; CLAES, Kathleen; MARTIN, Yolanda; KORF, Bruce R.; LEGIUS, Eric; MESSIAEN, Ludwine M.Neurofibromatosis type 1 (NF1), a common genetic disorder with a birth incidence of 1: 2,000-3,000, is characterized by a highly variable clinical presentation. To date, only two clinically relevant intragenic genotype-phenotype correlations have been reported for NF1 missense mutations affecting p. Arg1809 and a single amino acid deletion p.Met922del. Both variants predispose to a distinct mild NF1 phenotype with neither externally visible cutaneous/plexiform neurofibromas nor other tumors. Here, we report 162 individuals (129 unrelated probands and 33 affected relatives) heterozygous for a constitutional missense mutation affecting one of five neighboring NF1 codons-Leu844, Cys845, Ala846, Leu847, and Gly848-located in the cysteine-serine-rich domain (CSRD). Collectively, these recurrent missense mutations affect similar to 0.8% of unrelated NF1 mutation-positive probands in the University of Alabama at Birmingham (UAB) cohort. Major superficial plexiform neurofibromas and symptomatic spinal neurofibromas were more prevalent in these individuals compared with classic NF1-affected cohorts (both p < 0.0001). Nearly half of the individuals had symptomatic or asymptomatic optic pathway gliomas and/or skeletal abnormalities. Additionally, variants in this region seem to confer a high predisposition to develop malignancies compared with the general NF1-affected population (p = 0.0061). Our results demonstrate that these NF1 missense mutations, although located outside the GAP-related domain, may be an important risk factor for a severe presentation. A genotype-phenotype correlation at the NF1 region 844-848 exists and will be valuable in the management and genetic counseling of a significant number of individuals.
- Bi-allelic Variants in TONSL Cause SPONASTRIME Dysplasia and a Spectrum of Skeletal Dysplasia Phenotypes(2019) BURRAGE, Lindsay C.; REYNOLDS, John J.; BARATANG, Nissan Vida; PHILLIPS, Jennifer B.; WEGNER, Jeremy; MCFARQUHAR, Ashley; HIGGS, Martin R.; CHRISTIANSEN, Audrey E.; LANZA, Denise G.; SEAVITT, John R.; JAIN, Mahim; LI, Xiaohui; PARRY, David A.; RAMAN, Vandana; CHITAYAT, David; CHINN, Ivan K.; BERTUCH, Alison A.; KARAVITI, Lefkothea; SCHLESINGER, Alan E.; EARL, Dawn; BAMSHAD, Michael; SAVARIRAYAN, Ravi; DODDAPANENI, Harsha; MUZNY, Donna; JHANGIANI, Shalini N.; ENG, Christine M.; GIBBS, Richard A.; BI, Weimin; EMRICK, Lisa; ROSENFELD, Jill A.; POSTLETHWAIT, John; WESTERFIELD, Monte; DICKINSON, Mary E.; BEAUDET, Arthur L.; RANZA, Emmanuelle; HUBER, Celine; CORMIER-DAIRE, Valerie; SHEN, Wei; MAO, Rong; HEANEY, Jason D.; ORANGE, I. Jordan S.; BERTOLA, Debora; YAMAMOTO, Guilherme L.; BARATELA, Wagner Ar; BUTLER, Merlin G.; ALI, Asim; ADELI, Mehdi; COHN, Daniel H.; KRAKOW, Deborah; JACKSON, Andrew P.; LEES, Melissa; OFFIAH, Amaka C.; CARLSTON, Colleen M.; CAREY, John C.; STEWART, Grant S.; BACINO, Carlos A.; CAMPEAU, Philippe M.; LEE, BrendanSPONASTRIME dysplasia is an autosomal-recessive spondyloepimetaphyseal dysplasia characterized by spine (spondylar) abnormalities, midface hypoplasia with a depressed nasal bridge, metaphyseal striations, and disproportionate short stature. Scoliosis, coxa vara, childhood cataracts, short dental roots, and hypogammaglobulinemia have also been reported in this disorder. Although an autosomal-recessive inheritance pattern has been hypothesized, pathogenic variants in a specific gene have not been discovered in individuals with SPONASTRIME dysplasia. Here, we identified bi-allelic variants in TONSL, which encodes the Tonsoku-like DNA repair protein, in nine subjects (from eight families) with SPONASTRIME dysplasia, and four subjects (from three families) with short stature of varied severity and spondylometaphyseal dysplasia with or without immunologic and hematologic abnormalities, but no definitive metaphyseal striations at diagnosis. The finding of early embryonic lethality in a Tonsl(-/-) murine model and the discovery of reduced length, spinal abnormalities, reduced numbers of neutrophils, and early lethality in a tonsl(-/-) zebrafish model both support the hypomorphic nature of the identified TONSL variants. Moreover, functional studies revealed increased amounts of spontaneous replication fork stalling and chromosomal aberrations, as well as fewer camptothecin (CPT)-induced RAD51 foci in subject-derived cell lines. Importantly, these cellular defects were rescued upon re-expression of wild-type (WT) TONSL; this rescue is consistent with the hypothesis that hypomorphic TONSL variants are pathogenic. Overall, our studies in humans, mice, zebrafish, and subject-derived cell lines confirm that pathogenic variants in TONSL impair DNA replication and homologous recombination-dependent repair processes, and they lead to a spectrum of skeletal dysplasia phenotypes with numerous extra-skeletal manifestations.
- Mutations in the Human UBR1 Gene and the Associated Phenotypic Spectrum(2014) SUKALO, Maja; FIEDLER, Ariane; GUZMAN, Celina; SPRANGER, Stephanie; ADDOR, Marie-Claude; MCHEIK, Jiad N.; BENAVENT, Manuel Oltra; COBBEN, Jan M.; GILLIS, Lynette A.; SHEALY, Amy G.; DESHPANDE, Charu; BOZORGMEHR, Bita; EVERMAN, David B.; STATTIN, Eva-Lena; LIEBELT, Jan; KELLER, Klaus-Michael; BERTOLA, Debora Romeo; KARNEBEEK, Clara D. M. van; BERGMANN, Carsten; LIU, Zhifeng; DUEKER, Gesche; REZAEI, Nima; ALKURAYA, Fowzan S.; OGUR, Gonul; ALRAJOUDI, Abdullah; VENEGAS-VEGA, Carlos A.; VERBEEK, Nienke E.; RICHMOND, Erick J.; KIRBIYIK, Ozgur; RANGANATH, Prajnya; SINGH, Ankur; GODBOLE, Koumudi; ALI, Fouad A. M.; ALVES, Cresio; MAYERLE, Julia; LERCH, Markus M.; WITT, Heiko; ZENKER, MartinJohanson-Blizzard syndrome (JBS) is a rare, autosomal recessive disorder characterized by exocrine pancreatic insufficiency, typical facial features, dental anomalies, hypothyroidism, sensorineural hearing loss, scalp defects, urogenital and anorectal anomalies, short stature, and cognitive impairment of variable degree. This syndrome is caused by a defect of the E3 ubiquitin ligase UBR1, which is part of the proteolytic N-end rule pathway. Herein, we review previously reported (n=29) and a total of 31 novel UBR1 mutations in relation to the associated phenotype in patients from 50 unrelated families. Mutation types include nonsense, frameshift, splice site, missense, and small in-frame deletions consistent with the hypothesis that loss of UBR1 protein function is the molecular basis of JBS. There is an association of missense mutations and small in-frame deletions with milder physical abnormalities and a normal intellectual capacity, thus suggesting that at least some of these may represent hypomorphic UBR1 alleles. The review of clinical data of a large number of molecularly confirmed JBS cases allows us to define minimal clinical criteria for the diagnosis of JBS. For all previously reported and novel UBR1 mutations together with their clinical data, a mutation database has been established at LOVD.
- Genotype and phenotype spectrum of NRAS germline variants(2017) ALTMUELLER, Franziska; LISSEWSKI, Christina; BERTOLA, Debora; FLEX, Elisabetta; STARK, Zornitza; SPRANGER, Stephanie; BAYNAM, Gareth; BUSCARILLI, Michelle; DYACK, Sarah; GILLIS, Jane; YNTEMA, Helger G.; PANTALEONI, Francesca; LOON, Rosa L. E. van; MACKAY, Sara; MINA, Kym; SCHANZE, Ina; TAN, Tiong Yang; WALSH, Maie; WHITE, Susan M.; NIEWISCH, Marena R.; GARCIA-MINAUR, Sixto; PLAZA, Diego; AHMADIAN, Mohammad Reza; CAVE, Helene; TARTAGLIA, Marco; ZENKER, MartinRASopathies comprise a group of disorders clinically characterized by short stature, heart defects, facial dysmorphism, and varying degrees of intellectual disability and cancer predisposition. They are caused by germline variants in genes encoding key components or modulators of the highly conserved RAS-MAPK signalling pathway that lead to dysregulation of cell signal transmission. Germline changes in the genes encoding members of the RAS subfamily of GTPases are rare and associated with variable phenotypes of the RASopathy spectrum, ranging from Costello syndrome (HRAS variants) to Noonan and Cardiofaciocutaneous syndromes (KRAS variants). A small number of RASopathy cases with disease-causing germline NRAS alterations have been reported. Affected individuals exhibited features fitting Noonan syndrome, and the observed germline variants differed from the typical oncogenic NRAS changes occurring as somatic events in tumours. Here we describe 19 new cases with RASopathy due to disease-causing variants in NRAS. Importantly, four of them harbored missense changes affecting Gly12, which was previously described to occur exclusively in cancer. The phenotype in our cohort was variable but well within the RASopathy spectrum. Further, one of the patients (c. 35G > A; p.(Gly12Asp)) had a myeloproliferative disorder, and one subject (c. 34G > C; p.(Gly12Arg)) exhibited an uncharacterized brain tumour. With this report, we expand the genotype and phenotype spectrum of RASopathy-associated germline NRAS variants and provide evidence that NRAS variants do not spare the cancer-associated mutation hotspots.
- Biallelic variants in DNA2 cause poikiloderma with congenital cataracts and severe growth failure reminiscent of Rothmund-Thomson syndrome(2023) LAZZARO FILHO, Ricardo Di; YAMAMOTO, Guilherme Lopes; SILVA, Tiago J.; ROCHA, Leticia A.; LINNENKAMP, Bianca D. W.; CASTRO, Matheus Augusto Araujo; BARTHOLDI, Deborah; SCHALLER, Andre; LEEB, Tosso; KELMANN, Samantha; UTAGAWA, Claudia Y.; STEINER, Carlos E.; STEINMETZ, Leandra; HONJO, Rachel Sayuri; KIM, Chong Ae; WANG, Lisa; ABOURJAILI-BILODEAU, Raphael; CAMPEAU, Philippe; WARMAN, Matthew; PASSOS-BUENO, Maria Rita; HOCH, Nicolas C.; BERTOLA, Debora RomeoRothmund-Thomson syndrome (RTS) is a rare, heterogeneous autosomal recessive genodermatosis, with poikiloderma as its hallmark. It is classified into two types: type I, with biallelic variants in ANAPC1 and juvenile cataracts, and type II, with biallelic variants in RECQL4, increased cancer risk and no cataracts. We report on six Brazilian probands and two siblings of Swiss/Portuguese ancestry presenting with severe short stature, widespread poikiloderma and congenital ocular anomalies. Genomic and functional analysis revealed compound heterozygosis for a deep intronic splicing variant in trans with loss of function variants in DNA2, with reduction of the protein levels and impaired DNA double-strand break repair. The intronic variant is shared by all patients, as well as the Portuguese father of the European siblings, indicating a probable founder effect. Biallelic variants in DNA2 were previously associated with microcephalic osteodysplastic primordial dwarfism. Although the individuals reported here present a similar growth pattern, the presence of poikiloderma and ocular anomalies is unique. Thus, we have broadened the phenotypical spectrum of DNA2 mutations, incorporating clinical characteristics of RTS. Although a clear genotype-phenotype correlation cannot be definitively established at this moment, we speculate that the residual activity of the splicing variant allele could be responsible for the distinct manifestations of DNA2-related syndromes.