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Additional file 1: Fifteen supporting Figures S1-S15. A figure caption for each is given within the file.

Presentation of poster 679A at TAGC 2020 online. File include a PDF of the poster (Yusuff TAGC 2020 poster.PDF).

Introducción: la fibrosis quística (FQ) es una enfermedad hereditaria autosómica recesiva causada por mutaciones en el gen que codifica una proteína con función de canal de cloruro (CFTR). Se manifiesta como una enfermedad multiorgánica y se caracteriza por una gran heterogeneidad clínica. Existen pacientes que no manifiestan las características clínicas de la forma clásica y se describen como FQ atípica o no clásica. El diagnóstico se basa en un fenotipo clínico consistente más evidencia de disfunción del canal CFTR y/o en la identificación de dos mutaciones causantes de FQ. Ninguna de estas definiciones es suficiente por sí misma para establecer el diagnóstico. Objetivos: mostrar algunas limitaciones de los estudios de genética molecular en el proceso diagnóstico de FQ. Material y método: se consideran cinco casos clínicos de niños referidos con dato clínico de probable FQ y solicitud de estudio genético para la confirmación diagnóstica. Resultados: los estudios realizados no permiten confirmar el diagnóstico de FQ ni descartar un posible diagnóstico de FQ atípica. Conclusiones: la mayoría de las veces el diagnóstico de FQ es claro y los estudios genéticos permiten la confirmación diagnóstica, el asesoramiento genético y eventual diagnóstico prenatal. Sin embargo, el uso y la interpretación de los análisis genéticos presentan diversas dificultades relacionadas con la condición clínico-paraclínica del paciente, las limitaciones técnicas y la elección del conjunto de mutaciones a ser analizadas, especialmente en los casos de FQ atípica. Este trabajo muestra el desafío que puede implicar para el clínico interpretar un resultado molecular e integrarlo en el proceso diagnóstico de FQ. Summary Introduction: cystic fibrosis is an autosomal recessive hereditary disease caused by mutations of the gene which encodes a protein with a CFTR chloride channel function. It appears as a multi-organ disease and is characterized by a great clinical heterogeneity. There are patients who do not evidence the classic clinical characteristics and are described as atypical or non-classic cystic fibrosis. Diagnosis is based on a consistent clinical phenotype and evidence of dysfunction in the CFTR channel and/or in the identification of two mutations causing cystic fibrosis. None of these definitions is enough in itself to confirm diagnosis. Objectives: to show a few limitations on the molecular genetic studies in the cystic fibrosis diagnostic process Method: five clinical cases of children referred with clinical data of probable cystic fibrosis were considered, and they were requested a genetic study to confirm diagnosis Results: studies conducted do not enable the confirmation of cystic fibrosis diagnosis and neither do they allow discarding a possible diagnosis of atypical cystic fibrosis. Conclusions: in most cases the diagnosis of cystic fibrosis is clear and genetic studies enable the confirmation of diagnosis, genetic counseling and the final prenatal diagnosis. However, use and interpretation of genetic analysis result in several difficulties regarding the clinical and paraclinical characteristics of patients, technical limitations and choosing the mutations to be analysed, especially in the case of atypical cystic fibrosis. The present study shows the challenge faced by clinicians when interpreting a molecular result to incorporate it into the cystic fibrosis diagnostic process. Resumo Introdução: a fibrose cística FC é uma doença hereditária autossômica recessiva causada por mutações no gene que codifica uma proteína com função nos canais de cloretos CFTR. É uma doença com manifestações múltiplas e se caracteriza por apresentar-se com grande variedade clínica. Alguns pacientes não apresentam as características clínicas clássicas e nesses casos a doença é chamada FC atípica ou não clássica. O diagnóstico é feito através do fenótipo clínico mais consistente associado a evidencia de disfunção do canal CFTR e/ou na identificação de duas mutações causadoras da FC. Nenhuma dessas definições é suficiente para estabelecer o diagnóstico. Objetivos: mostrar algumas limitações dos estudos de genética molecular no diagnóstico de FC. Material e método: são discutidos cinco casos clínicos de crianças referidas com historia clínica de FC provável e pedido de estudo genético para confirmação do diagnóstico. Resultados: os estudos realizados não permitem confirmar o diagnóstico de FC nem descartar um possível diagnóstico de FC atípica. Conclusões: na maioria dos casos o diagnóstico de FC é claro e os estudos genéticos permitem confirmar o diagnóstico, o assessoramento genético e eventual diagnóstico pré-natal. No entanto, o emprego e a interpretação das análises genéticas apresentam varias dificuldades relacionadas com a condição clínica do paciente, as limitações técnicas e a escolha do conjunto de mutações a ser estudadas, especialmente nos casos de fibrose cística atípica. Este trabalho mostra o desafio que o médico clínico enfrenta para interpretar um resultado molecular e integrá-lo ao processo de diagnóstico de FC.

Duplications at 15q11.2-q13.3 overlapping the Prader-Willi/Angelman syndrome (PWS/AS) region have been associated with developmental delay (DD), autism spectrum disorder (ASD) and schizophrenia (SZ). Due to presence of imprinted genes within the region, the parental origin of these duplications may be key to the pathogenicity. Duplications of maternal origin are associated with disease, whereas the pathogenicity of paternal ones is unclear. To clarify the role of maternal and paternal duplications, we conducted the largest and most detailed study to date of parental origin of 15q11.2-q13.3 interstitial duplications in DD, ASD and SZ cohorts. We show, for the first time, that paternal duplications lead to an increased risk of developing DD/ASD/multiple congenital anomalies (MCA), but do not appear to increase risk for SZ. The importance of the epigenetic status of 15q11.2-q13.3 duplications was further underlined by analysis of a number of families, in which the duplication was paternally derived in the mother, who was unaffected, whereas her offspring, who inherited a maternally derived duplication, suffered from psychotic illness. Interestingly, the most consistent clinical characteristics of SZ patients with 15q11.2-q13.3 duplications were learning or developmental problems, found in 76% of carriers. Despite their lower pathogenicity, paternal duplications are less frequent in the general population with a general population prevalence of 0.0033% compared to 0.0069% for maternal duplications. This may be due to lower fecundity of male carriers and differential survival of embryos, something echoed in the findings that both types of duplications are de novo in just over 50% of cases. Isodicentric chromosome 15 (idic15) or interstitial triplications were not observed in SZ patients or in controls. Overall, this study refines the distinct roles of maternal and paternal interstitial duplications at 15q11.2-q13.3, underlining the critical importance of maternally expressed imprinted genes in the contribution of Copy Number Variants (CNVs) at this interval to the incidence of psychotic illness. This work will have tangible benefits for patients with 15q11.2-q13.3 duplications by aiding genetic counseling., Author Summary The genetic interval 15q11.2-q13.3 on human chromosome 15 contains several so-called “imprinted genes” which are subject to epigenetic marking leading to activity from only one parental copy. This is in contrast to non-imprinted genes, whose activity is independent of their parent-of-origin. Deletions affecting the 15q11.2-q13.3 interval cause Prader-Willi and Angelman syndromes (PWS/AS), depending on whether the deletions are paternally or maternally derived respectively. Duplications at the PWS/AS interval region may also lead to neurodevelopmental disorders, including developmental delay (DD), autism spectrum disorder (ASD) and schizophrenia (SZ). Due to presence of imprinted genes within the region, the parental origin of these duplications may be key to the pathogenicity. We show, for the first time, that paternal duplications lead to an increased risk of developing DD/ASD/multiple congenital anomalies (MCA) but, unlike maternal duplication, do not appear to increase risk for SZ. This study refines the distinct roles of maternal and paternal duplications at 15q11.2-q13.3, underlining the critical importance of maternally active imprinted genes in the contribution to the incidence of psychotic illness. This work will have tangible benefits for patients with 15q11.2-q13.3 duplications by aiding genetic counseling.

Orientador: Dra. Mónica Marín. Co-orientador: Dra. Arlinet Kierbel. Co-orientador: Dra. Alicia Vaglio.

We examined more than 38,000 spouse pairs from four neurodevelopmental disease cohorts and the UK Biobank to identify phenotypic and genetic patterns in parents associated with neurodevelopmental disease risk in children. We identified correlations between six phenotypes in parents and children, including correlations of clinical diagnoses such as obsessive-compulsive disorder (R=0.31-0.49, p<0.001), and two measures of sub-clinical autism features in parents affecting several autism severity measures in children, such as bi-parental mean Social Responsiveness Scale (SRS) scores affecting proband SRS scores (regression coefficient=0.11, p=0.003). We further describe patterns of phenotypic and genetic similarity between spouses, where spouses show both within- and cross-disorder correlations for seven neurological and psychiatric phenotypes, including a within-disorder correlation for depression (R=0.25-0.72, p<0.001) and a cross-disorder correlation between schizophrenia and personality disorder (R=0.20-0.57, p<0.001). Further, these spouses with similar phenotypes were significantly correlated for rare variant burden (R=0.07-0.57, p<0.0001). We propose that assortative mating on these features may drive the increases in genetic risk over generations and the appearance of "genetic anticipation" associated with many variably expressive variants. We further identified parental relatedness as a risk factor for neurodevelopmental disorders through its inverse correlations with burden and pathogenicity of rare variants and propose that parental relatedness drives disease risk by increasing genome-wide homozygosity in children (R=0.09-0.30, p<0.001). Our results highlight the utility of assessing parent phenotypes and genotypes in predicting features in children carrying variably expressive variants and counseling families carrying these variants.