Occurrence of cancer in Marfan syndrome: Report of two patients with neuroblastoma and review of the literature.

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder caused by pathogenic variants in FBN1, with a hitherto unknown association with cancer. Here, we present two females with MFS who developed pediatric neuroblastoma. Patient 1 presented with neonatal MFS and developed an adrenal neuroblastoma with unfavorable tumor genetics at 10 months of age. Whole genome sequencing revealed a germline de novo missense FBN1 variant (NP_000129.3:p.(Asp1322Asn)), resulting in intron 32 inclusion and exon 32 retention. Patient 2 was diagnosed with classic MFS, caused by a germline de novo frameshift variant in FBN1 (NP_000129.3:p.(Cys805Ter)). At 18 years, she developed high-risk neuroblastoma with a somatic ALK pathogenic variant (NP_004295.2:p.(Arg1275Gln)). We identified 32 reported cases of MFS with cancer in PubMed, yet none with neuroblastoma. Among patients, we observed an early cancer onset and high frequency of MFS complications. We also queried cancer databases for somatic FBN1 variants, finding 49 alterations reported in PeCan, and variants in 2% of patients in cBioPortal. In conclusion, we report the first two patients with MFS and neuroblastoma and highlight an early age at cancer diagnosis in reported patients with MFS. Further epidemiological and functional studies are needed to clarify the growing evidence linking MFS and cancer.

Equity in action: The Diagnostic Working Group of The Undiagnosed Diseases Network International.

Rare diseases are recognized as a global public health priority. A timely and accurate diagnosis is a critical enabler for precise and personalized health care. However, barriers to rare disease diagnoses are especially steep for those from historically underserved communities, including low- and middle-income countries. The Undiagnosed Diseases Network International (UDNI) was launched in 2015 to help fill the knowledge gaps that impede diagnosis for rare diseases, and to foster the translation of research into medical practice, aided by active patient involvement. To better pursue these goals, in 2021 the UDNI established the Diagnostic Working Group of the UDNI (UDNI DWG) as a community of practice that would (a) accelerate diagnoses for more families; (b) support and share knowledge and skills by developing Undiagnosed Diseases Programs, particularly those in lower resource areas; and (c) promote discovery and expand global medical knowledge. This Perspectives article documents the initial establishment and iterative co-design of the UDNI DWG.

Register-based and genetic studies of Prader-Willi syndrome show a high frequency of gonadal tumors and a possible mechanism for tumorigenesis through imprinting relaxation.

Prader-Willi syndrome (PWS) is a rare disease caused by a lack of expression of inherited imprinted genes in the paternally derived Prader-Willi critical region on chromosome 15q11.2-q13. It is characterized by poor feeding and hypotonia in infancy, intellectual disability, behavioral abnormalities, dysmorphic features, short stature, obesity, and hypogonadism. PWS is not a known cancer predisposition syndrome, but previous investigations regarding the prevalence of cancer in these patients suggest an increased risk of developing specific cancer types such as myeloid leukemia and testicular cancer. We present the results from a Swedish national population-based cohort study of 360 individuals with PWS and 18,000 matched comparisons. The overall frequency of cancer was not increased in our PWS cohort, but we found a high frequency of pediatric cancers. We also performed whole-genome sequencing of blood- and tumor-derived DNAs from a unilateral dysgerminoma in a 13-year-old girl with PWS who also developed bilateral ovarian sex cord tumors with annular tubules. In germline analysis, there were no additional findings apart from the 15q11.2-q13 deletion of the paternal allele, while a pathogenic activating KIT mutation was identified in the tumor. Additionally, methylation-specific multiplex ligation-dependent probe amplification revealed reduced methylation at the PWS locus in the dysgerminoma but not in the blood. In conclusion, our register-based study suggests an increased risk of cancer at a young age, especially testicular and ovarian tumors. We found no evidence of a general increase in cancer risk in patients with PWS. However, given our limited observational time, further studies with longer follow-up times are needed to clarify the lifetime cancer risk in PWS. We have also described the second case of locus-specific loss-of-imprinting in a germ cell tumor in PWS, suggesting a possible mechanism of carcinogenesis.

Family History and Warning Symptoms Precede Sudden Cardiac Death in Arrhythmogenic Right Ventricular Cardiomyopathy (from a Nationwide Study in Sweden).

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disease explaining about 4% of sudden cardiac death (SCD) cases in the young in Sweden. This study aimed to describe the circumstances preceding SCD in all victims <35 years of age who received an autopsy-confirmed diagnosis of ARVC from January 1, 2000, to December 31, 2010, in Sweden (n = 22). Data on demographics, medical and family history, circumstances of death, and anatomopathological findings were collected from several compulsory national health registries, clinical records, family interviews, and autopsy reports. Registry-based data were compared with age-matched, gender-matched, and geographically-matched population controls. During the 6 months preceding SCD, 15 cases (68%) had experienced symptoms of cardiac origin, mainly syncope or presyncope (54%) and chest discomfort (27%). A total of 8 cases (36%) had sought medical care because of cardiac symptoms. The occurrence of hospital visits was significantly increased in cases compared with controls (odds ratio 4.62 [1.35 to 15.8]). A total of 10 cases (45%) had a family history of SCD. The most common activity at the time of death was exercise (41%). A complete cardiac investigation was seldom performed; only 1 case was diagnosed with ARVC before death. In conclusion, in this nationwide study, we observed a high prevalence of symptoms of cardiac origin, healthcare use, and family history of SCD preceding SCD in the young caused by ARVC. Increased awareness of these warning signals in younger patients is critical to improving risk stratification and early disease detection.

Cohort profile: the Swedish study of SUDden cardiac Death in the Young (SUDDY) 2000-2010: a complete nationwide cohort of SCDs.

PURPOSE: The rationale behind the SUDden cardiac Death in the Young (SUDDY) cohort was to provide a complete nationwide, high-quality platform with integrated multisource data, for clinical and genetic research on sudden cardiac death (SCD) in the young, with the ultimate goal to predict and prevent SCD. PARTICIPANTS: The cohort contains all SCD victims <36 years, in Sweden during the period 2000-2010. We assigned five population-based controls per case, together with parents of cases and controls, in total 15 633 individuals. Data of all individuals were extracted from multiple mandatory registries; the National Patient Registry, the Medical Birth Registry, the Prescribed Drug registry, the Cause of Death registry, the Multigeneration Registry, combined with socioeconomic data from Statistics Sweden. From SCD victims, the autopsy report, medical records, ECGs, parental information and biological samples were gathered. FINDINGS TO DATE: We identified 903 individuals diagnosed with SCD (67% men, 33% women). The cases comprised 236 infants <1 year of age (26%), 90 individuals aged 1-15 years (10%), 186 individuals aged 15-25 years (21%) and 391 aged 25-35 years (43%). Hospitalisations and outpatient clinic visits due to syncope were significantly more common among cases than controls. DNA obtained from dried blood spots tests (DBS) stored from birth was equally suitable as venous blood samples for high-throughput genetic analysis of SCD cases. FUTURE PLANS: We will explore the SUDDY cohort for symptoms and healthcare consumption, socioeconomic variables and family history of SCD. Furthermore, we will perform whole exome sequencing analysis on DNA of cases obtained from DBS or postmortem samples together with parental blood samples in search for gene variants associated with cardiac disease. The genetic analysis together with data compiled in the nationwide cohort is expected to improve current knowledge on the incidence, aetiology, clinical characteristics and family history of SCD.

Genetic basis of Sjögren's syndrome. How strong is the evidence?

Sjögren's syndrome (SS) is a late-onset chronic autoimmune disease (AID) affecting the exocrine glands, mainly the salivary and lachrymal. Genetic studies on twins with primary SS have not been performed, and only a few case reports describing twins have been published. The prevalence of primary SS in siblings has been estimated to be 0.09% while the reported general prevalence of the disease is approximately 0.1%. The observed aggregation of AIDs in families of patients with primary SS is nevertheless supportive for a genetic component in its etiology. In the absence of chromosomal regions identified by linkage studies, research has focused on candidate gene approaches (by biological plausibility) rather than on positional approaches. Ancestral haplotype 8.1 as well as TNF, IL10 and SSA1 loci have been consistently associated with the disease although they are not specific for SS. In this review, the genetic component of SS is discussed on the basis of three known observations: (a) age at onset and sex-dependent presentation, (b) familial clustering of the disease, and (c) dissection of the genetic component. Since there is no strong evidence for a specific genetic component in SS, a large international and collaborative study would be suitable to assess the genetics of this disorder.

Epidemiología genética de la artritis reumatoide: ¿qué esperar de América Latina? / Genetic epidemiology of rheumatoid arthritis: What to expect from Latin America?

La artritis reumatoide es una enfermedad sistémica autoinmune, crónica, que afecta principalmente las articulaciones que tienen movimiento. La enfermedad es mucho más frecuente en mujeres y su prevalencia en la población latinoamericana es cercana al 0,5 por ciento. La existencia de agregación familiar (ls= 2-17) indica su carácter hereditario. Sin embargo, la herencia de la artritis reumatoide es poligénica y no sigue un patrón mendeliano. La importancia de encontrar factores genéticos asociados con la artritis reumatoide radica en la contribución a la comprensión de los mecanismos patogénicos de la enfermedad, su posible aplicación clínica como marcadores de riesgo, diagnóstico, pronóstico, e incluso, blanco terapéutico. Mapeos genéticos llevados a cabo en diversas poblaciones en busca de loci y genes candidatos han identificado la región HLA como aquella con mayor evidencia de ligamento. Sin embargo, su fracción etiológica corresponde sólo a un tercio de la susceptibilidad genética de la enfermedad. Esto indica que genes diferentes al HLA también están implicados en la susceptibilidad a desarrollar artritis reumatoide. En Latinoamérica, los alelos HLA-DRB1*0404 y TNF -308A han sido asociados de manera uniforme con la artritis reumatoide. En el presente artículo se revisan los factores genéticos de la artritis reumatoide en el marco de una aproximación lógica y ordenada establecida por la epidemiología genética, y se ofrecen algunas recomendaciones para futuros estudios en poblaciones latinoamericanas.

Rheumatoid arthritis is a chronic and systemic autoimmune disease characterized by inflammation and destruction of the synovial joints. It affects approximately 0.5% of the Latin- American population and is three times more common in women than in men. Evidence of familial aggregation (ls=2-17) was the first indication of a genetic susceptibility to disease. As in other autoimmune diseases, it has a complex genetic basis. Results from whole-genome scans indicate that the HLA region contains a significant and consistent set of linked loci. However, HLA accounts for only one-third of the genetic susceptibility of disease, indicating that non-HLA genes are also involved in the disease susceptibility. In Latin-America, association with HLA-DRB1*0404 and TNF -308A alleles has been uniformly established; however, many other candidate genes remain to be studied. The identification of genetic factors conferring susceptibility to rheumatoid arthritis will contribute to the knowledge of the pathogenic mechanisms, ability to predict its occurrence, the development of diagnostic tools, prognosis, and treatment. The genetic epidemiology of rheumatoid arthritis is herein reviewed; a set of recommendations is provided for the design, analysis and interpretation of genetic association studies in the context of Latin-American populations.

[Genetic epidemiology of rheumatoid arthritis: what to expect from Latin America?]. / Epidemiología genética de la artritis reumatoide: qué esperar de América Latina?

Rheumatoid arthritis is a chronic and systemic autoimmune disease characterized by inflammation and destruction of the synovial joints. It affects approximately 0.5% of the Latin-American population and is three times more common in women than in men. Evidence of familial aggregation (lambdas=2-17) was the first indication of a genetic susceptibility to disease. As in other autoimmune diseases, it has a complex genetic basis. Results from whole-genome scans indicate that the HLA region contains a significant and consistent set of linked loci. However, HLA accounts for only one-third of the genetic susceptibility of disease, indicating that non-HLA genes are also involved in the disease susceptibility. In Latin-America, association with HLA-DRB1*0404 and TNF -308A alleles has been uniformly established; however, many other candidate genes remain to be studied. The identification of genetic factors conferring susceptibility to rheumatoid arthritis will contribute to the knowledge of the pathogenic mechanisms, ability to predict its occurrence, the development of diagnostic tools, prognosis, and treatment. The genetic epidemiology of rheumatoid arthritis is herein reviewed; a set of recommendations is provided for the design, analysis and interpretation of genetic association studies in the context of Latin-American populations.