Emerging variants, unique phenotypes, and transcriptomic signatures: an integrated study of COASY-associated diseases.

OBJECTIVE: COASY, the gene encoding the bifunctional enzyme CoA synthase, which catalyzes the last two reactions of cellular de novo coenzyme A (CoA) biosynthesis, has been linked to two exceedingly rare autosomal recessive disorders, such as COASY protein-associated neurodegeneration (CoPAN), a form of neurodegeneration with brain iron accumulation (NBIA), and pontocerebellar hypoplasia type 12 (PCH12). We aimed to expand the phenotypic spectrum and gain insights into the pathogenesis of COASY-related disorders. METHODS: Patients were identified through targeted or exome sequencing. To unravel the molecular mechanisms of disease, RNA sequencing, bioenergetic analysis, and quantification of critical proteins were performed on fibroblasts. RESULTS: We identified five new individuals harboring novel COASY variants. While one case exhibited classical CoPAN features, the others displayed atypical symptoms such as deafness, language and autism spectrum disorders, brain atrophy, and microcephaly. All patients experienced epilepsy, highlighting its potential frequency in COASY-related disorders. Fibroblast transcriptomic profiling unveiled dysregulated expression in genes associated with mitochondrial respiration, responses to oxidative stress, transmembrane transport, various cellular signaling pathways, and protein translation, modification, and trafficking. Bioenergetic analysis revealed impaired mitochondrial oxygen consumption in COASY fibroblasts. Despite comparable total CoA levels to control cells, the amounts of mitochondrial 4'-phosphopantetheinylated proteins were significantly reduced in COASY patients. INTERPRETATION: These results not only extend the clinical phenotype associated with COASY variants but also suggest a continuum between CoPAN and PCH12. The intricate interplay of altered cellular processes and signaling pathways provides valuable insights for further research into the pathogenesis of COASY-associated diseases.

An European overview of genetic counselling supervision provision.

Genetic testing is becoming more commonplace in general and specialist health care, and should always be accompanied by genetic counselling, according to legislation in many European countries and recommendations by professional bodies. Personal and professional competence is necessary to provide safe and effective genetic counselling. Clinical and counselling supervision of genetics healthcare practitioners plays a key role in quality assurance, providing a safe environment not only for patients but for professionals too. However, in many European countries, genetic counsellors are still an emerging professional group and counselling supervision is not routinely offered and there are no enough evidences on the impact of these insufficiencies. This study aimed to explore the current status of genetic counselling supervision provision across Europe and to ascertain factors that might be relevant for the successful implementation of counselling supervision. A total of 100 practitioners responded to an online survey; respondents were from 18 countries, with the majority working in France (27%) and Spain (17%). Only 34 participants reported having access to genetic counselling supervision. Country of origin, the existence of a regulation system and years of experience were factors identified as relevant, influencing access and characteristics of counselling supervision. Although there is a growing number of genetic counsellors trained at European level, just a few countries have implemented and required as mandatory the access to genetic counselling supervision. Nevertheless, this is essential to ensure a safe and effective genetic counselling and should be regulated at the European genetic healthcare services.

Erratum zu: Über die Notwendigkeit der Anerkennung von sog. Kernberufsgruppen innerhalb der genetischen Gesundheitsversorgung in Europa.

[This corrects the article DOI: 10.1515/medgen-2022-2116.].

Current Status of Genetic Counselling for Rare Diseases in Spain.

Genetic Counselling is essential for providing personalised information and support to patients with Rare Diseases (RD). Unlike most other developed countries, Spain does not recognize geneticists or genetic counsellors as healthcare professionals Thus, patients with RD face not only challenges associated with their own disease but also deal with lack of knowledge, uncertainty, and other psychosocial issues arising as a consequence of diagnostic delay. In this review, we highlight the importance of genetic counsellors in the field of RD as well as evaluate the current situation in which rare disease patients receive genetic services in Spain. We describe the main units and strategies at the national level assisting patients with RD and we conclude with a series of future perspectives and unmet needs that Spain should overcome to improve the management of patients with RD.

Beyond the disease itself: A cross-cutting educational initiative for patients and families with rare diseases.

Rare diseases (RDs) as a whole affect a huge number of individuals although each specific condition comprises a low number of individuals. As a consequence, funds allocated to expand research to all conditions are often limited. Several initiatives have emerged to invest more resources for research in RDs, but patients express unmet needs regarding educational initiatives, awareness support, and psychosocial resources. We developed an educational training program in the format of weekly sessions covering basic medical scientific knowledge and psychosocial aspects of RDs. The aim of this initiative was to assess its overall impact regarding knowledge, psychological issues, and participant satisfaction. Items were evaluated through surveys before and after the sessions. Here, we report the experience and impact of two editions of this initiative with a total of 37 participants. Our results show improvements in knowledge and better management of the psychological impact. Moreover, participants were able to exchange experiences and concerns, most of which were shared even though the RDs were different. Overall, the program was evaluated by the participants as a highly beneficial experience and all of them were interested in attending advanced editions.

Integración del asesor genético en el modelo asistencial multidisciplinar en genética clínica y cáncer hereditario / Genetic counsellors in a multidisciplinary model of clinical genetics and hereditary cancer

No disponible

Heterozygous rare genetic variants in non-syndromic early-onset obesity.

BACKGROUND: Obesity is a very heterogeneous disorder at both the clinical and molecular levels and with high heritability. Several monogenic forms and genes with strong effects have been identified for non-syndromic severe obesity. Novel therapeutic interventions are in development for some genetic forms, emphasizing the importance of determining genetic contributions. OBJECTIVE: We aimed to define the contribution of rare single-nucleotide genetic variants (RSVs) in candidate genes to non-syndromic severe early-onset obesity (EOO; body mass index (BMI) >+3 standard deviation score, <3 years). METHODS: Using a pooled DNA-sequencing approach, we screened for RSVs in 15 obesity candidate genes in a series of 463 EOO patients and 480 controls. We also analysed exome data from 293 EOO patients from the "Viva la Familia" (VLF) study as a replication dataset. RESULTS: Likely or known pathogenic RSVs were identified in 23 patients (5.0%), with 7 of the 15 genes (BDNF, FTO, MC3R, MC4R, NEGR1, PPARG and SIM1) harbouring RSVs only in cases (3.67%) and none in controls. All were heterozygous changes, either de novo (one in BDNF) or inherited from obese parents (seven maternal, three paternal), and no individual carried more than one variant. Results were replicated in the VLF study, where 4.10% of probands carried RSVs in the overrepresented genes. RSVs in five genes were either absent (LEP) or more common in controls than in cases (ADRB3, LEPR, PCSK1 and PCSK2) in both obese datasets. CONCLUSIONS: Heterozygous RSVs in several candidate genes of the melanocortin pathway are found in ~5.0% patients with EOO. These results support the clinical utility of genetic testing to identify patients who might benefit from targeted therapeutic intervention.

Psychiatric genetic counseling: A mapping exercise.

Psychiatric genetic counseling (PGC) is gradually developing globally, with countries in various stages of development. In some, PGC is established as a service or as part of research projects while in others, it is just emerging as a concept. In this article, we describe the current global landscape of this genetic counseling specialty and this field's professional development. Drawing on information provided by expert representatives from 16 countries, we highlight the following: (a) current understanding of PGC; (b) availability of services for patients; (c) availability of training; (d) healthcare system disparities and cultural differences impacting practice; and (e) anticipated challenges going forward.

Perspectives in genetic counseling for spinal muscular atrophy in the new therapeutic era: early pre-symptomatic intervention and test in minors.

Spinal muscular atrophy (SMA) is an autosomal-recessive neuromuscular disorder representing a continuous spectrum of muscular weakness ranging from compromised neonates to adults with minimal manifestations. Patients show homozygous absence or disease-causing variants of the SMN1 gene (-/- or 0/0) and in carriers only one copy is absent or mutated (1/0). Genetic diagnosis and counseling in SMA present several challenges, including the existence of carriers (2/0) that are undistinguishable of non-carriers (1/1) with current genetic testing methods and the report of patients (0/0) with very mild manifestations and even asymptomatic that are discovered when a full symptomatic case appears in the family. Younger asymptomatic siblings of symptomatic SMA patients are usually never tested until adolescence or adult life. However, following regulatory approval of the first tailored treatment for SMA, the prospects for care of these patients have changed. Early testing, including pre-symptomatic newborn screening and confirmation of diagnosis would change proactive measures and opportunities for therapy based in the actual landscape of new treatments. This review discusses the challenges and new perspectives of genetic counseling in SMA.

Utility of two SMN1 variants to improve spinal muscular atrophy carrier diagnosis and genetic counselling.

Spinal muscular atrophy (SMA) is caused by deletions/mutations in SMN1. Most heterozygous SMA carriers have only one SMN1 copy in one of the alleles (1/0 carriers). However, a few carriers lack SMN1 in one of their chromosomes, but present two gene copies in the other. These "2/0 carriers" are undistinguishable from non-carrier individuals (1/1) with currently available methods. Previous association of SMN1 variants c.*3 + 80 T > G and c.*211_*212del with two SMN1 copies in cis in Ashkenazi population prompted us to analyze them in 270 Spanish individuals (SMA carriers, patients and general population). Both variants were much more frequently detected in chromosomes with 2 SMN1 copies in cis in comparison with chromosomes carrying one copy (17.9 vs. 0.7%; p < 0.001). In particular, one-fifth of 2/0 SMA carriers harboured one or both variants compared to none of 99 non-carriers with two SMN1 copies (p < 0.001). The c.*211_*212del variant was also much more frequent in exon 8 of SMN2-SMN1 hybrids than in that of intact SMN1 genes (20 vs. 0.83%, p < 0.001), suggesting its association with chromosomal rearrangements. Although absence of these variants does not exclude that a particular individual is a 2/0 SMA carrier, their presence is valuable to substantially increase residual risk in putative carriers, thus improving genetic counselling.

Provision of Genetic Services for Autism and its Impact on Spanish Families.

Although a genetic evaluation can identify the etiology in 15-30% of individuals with autism spectrum disorder, several studies show an underuse of genetic services by affected families. We have explored the access to genetic services and perception of genetics and recurrence risk in parents of autistic children in Spain. Despite the high interest in genetics, our results show a remarkable underutilization of genetic services, with only 30% of families having visited a genetic service and 13% of patients having undergone the recommended genetic test. This poor service provision influenced recurrence risk perception and had a great impact on family planning. The National Health System should ensure their access to genetic services allowing them to take informed decisions with precise information.

Novel genes involved in severe early-onset obesity revealed by rare copy number and sequence variants.

Obesity is a multifactorial disorder with high heritability (50-75%), which is probably higher in early-onset and severe cases. Although rare monogenic forms and several genes and regions of susceptibility, including copy number variants (CNVs), have been described, the genetic causes underlying the disease still remain largely unknown. We searched for rare CNVs (>100kb in size, altering genes and present in <1/2000 population controls) in 157 Spanish children with non-syndromic early-onset obesity (EOO: body mass index >3 standard deviations above the mean at <3 years of age) using SNP array molecular karyotypes. We then performed case control studies (480 EOO cases/480 non-obese controls) with the validated CNVs and rare sequence variants (RSVs) detected by targeted resequencing of selected CNV genes (n = 14), and also studied the inheritance patterns in available first-degree relatives. A higher burden of gain-type CNVs was detected in EOO cases versus controls (OR = 1.71, p-value = 0.0358). In addition to a gain of the NPY gene in a familial case with EOO and attention deficit hyperactivity disorder, likely pathogenic CNVs included gains of glutamate receptors (GRIK1, GRM7) and the X-linked gastrin-peptide receptor (GRPR), all inherited from obese parents. Putatively functional RSVs absent in controls were also identified in EOO cases at NPY, GRIK1 and GRPR. A patient with a heterozygous deletion disrupting two contiguous and related genes, SLCO4C1 and SLCO6A1, also had a missense RSV at SLCO4C1 on the other allele, suggestive of a recessive model. The genes identified showed a clear enrichment of shared co-expression partners with known genes strongly related to obesity, reinforcing their role in the pathophysiology of the disease. Our data reveal a higher burden of rare CNVs and RSVs in several related genes in patients with EOO compared to controls, and implicate NPY, GRPR, two glutamate receptors and SLCO4C1 in highly penetrant forms of familial obesity.

Complementarity between medical geneticists and genetic counsellors: its added value in genetic services in Europe.

Clinical genetic services have progressed significantly the last few decades. This has led to the need for non-medical health-care professionals working as genetic counsellors in Europe and worldwide. However, there is no unified approach to genetic counsellors' role in health-care services in Europe, as in most countries the profession is still emerging and the educational backgrounds diverge noticeably, within and between countries. This qualitative study aims to describe the potential added value of genetic counsellors in clinical genetics teams and to explore their tasks and responsibilities in different European countries. A total of 143 participants providing genetic counselling in Europe at the time of the survey responded. The results show differences in activities of genetic counsellors, although there is a wide range of roles, which are similar. The ability to establish a quality relationship with consultands was frequently mentioned as one of the strengths of genetic counsellors, as well as a patient-centred approach. It is believed that genetic counsellors add a more holistic approach of psychosocial and familial dimensions of genetic concerns to the multidisciplinary teams. This study provides examples of successful integration of genetic counsellors in teams, as complementariness with medical geneticist became clear in several cases. Although the added value of genetic counsellors was manifested, professional recognition of genetic counsellors across Europe is still needed in order to support the quality of patients care and safety of practice.

The perceived impact of the European registration system for genetic counsellors and nurses.

The aim of the European Board of Medical Genetics has been to develop and promote academic and professional standards necessary in order to provide competent genetic counselling services. The aim of this study was to explore the impact of the European registration system for genetic nurses and counsellors from the perspectives of those professionals who have registered. Registration system was launched in 2013. A cross-sectional, online survey was used to explore the motivations and experiences of those applying for, and the effect of registration on their career. Fifty-five Genetic Nurses and Counsellors are registered till now, from them, thirty-three agreed to participate on this study. The main motivations for registering were for recognition of their work value and competence (30.3%); due to the absence of a registration system in their own country (15.2%) and the possibility of obtaining a European/international certification (27.3%), while 27.3% of respondents registered to support recognition of the genetic counselling profession. Some participants valued the registration process as an educational activity in its own right, while the majority indicated the greatest impact of the registration process was on their clinical practice. The results confirm that registrants value the opportunity to both confirm their own competence and advance the genetic counselling profession in Europe.

Mutations in pregnancy-associated plasma protein A2 cause short stature due to low IGF-I availability.

Mutations in multiple genes of the growth hormone/IGF-I axis have been identified in syndromes marked by growth failure. However, no pathogenic human mutations have been reported in the six high-affinity IGF-binding proteins (IGFBPs) or their regulators, such as the metalloproteinase pregnancy-associated plasma protein A2 (PAPP-A2) that is hypothesized to increase IGF-I bioactivity by specific proteolytic cleavage of IGFBP-3 and -5. Multiple members of two unrelated families presented with progressive growth failure, moderate microcephaly, thin long bones, mildly decreased bone density and elevated circulating total IGF-I, IGFBP-3, and -5, acid labile subunit, and IGF-II concentrations. Two different homozygous mutations in PAPPA2, p.D643fs25* and p.Ala1033Val, were associated with this novel syndrome of growth failure. In vitro analysis of IGFBP cleavage demonstrated that both mutations cause a complete absence of PAPP-A2 proteolytic activity. Size-exclusion chromatography showed a significant increase in IGF-I bound in its ternary complex. Free IGF-I concentrations were decreased. These patients provide important insights into the regulation of longitudinal growth in humans, documenting the critical role of PAPP-A2 in releasing IGF-I from its BPs.