The Importance of Digging into the Genetics of SMN Genes in the Therapeutic Scenario of Spinal Muscular Atrophy

Estructura híbrida; Atrofia muscular espinal; Neurona motora de supervivencia 1Hybrid structure; Spinal muscular atrophy; Survival motor neuron 1Estructura híbrida; Atròfia muscular espinal; Neurona motora de supervivència 1After 26 years of discovery of the determinant survival motor neuron 1 and the modifier survival motor neuron 2 genes (SMN1 and SMN2, respectively), three SMN-dependent specific therapies are already approved by FDA and EMA and, as a consequence, worldwide SMA patients are currently under clinical investigation and treatment. Bi-allelic pathogenic variants (mostly deletions) in SMN1 should be detected in SMA patients to confirm the disease. Determination of SMN2 copy number has been historically employed to correlate with the phenotype, predict disease evolution, stratify patients for clinical trials and to define those eligible for treatment. In view that discordant genotype-phenotype correlations are present in SMA, besides technical issues with detection of SMN2 copy number, we have hypothesized that copy number determination is only the tip of the iceberg and that more deepen studies of variants, sequencing and structures of the SMN2 genes are necessary for a better understanding of the disease as well as to investigate possible influences in treatment responses. Here, we highlight the importance of a comprehensive approach of SMN1 and SMN2 genetics with the perspective to apply for better prediction of SMA in positive neonatal screening cases and early diagnosis to start treatments.This work was partially supported by Grants from Biogen and Roche (to E.F.T. supporting M.C.-R. and L.B.-P.), and from Spanish Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias and cofunded with ERDF funds (Grant No. FIS PI18/000687) (to E.F.T.)

Schuurs–Hoeijmakers Syndrome (PACS1 Neurodevelopmental Disorder): Seven Novel Patients and a Review

Síndrome de Schuurs-Hoeijmakers; Discapacitat intel·lectual; Trastorns rarsSíndrome de Schuurs-Hoeijmakers; Discapacidad intelectual; Trastornos rarosSchuurs–Hoeijmakers syndrome; Intellectual disability; Rare disordersSchuurs–Hoeijmakers syndrome (SHMS) or PACS1 Neurodevelopmental disorder is a rare disorder characterized by intellectual disability, abnormal craniofacial features and congenital malformations. SHMS is an autosomal dominant hereditary disease caused by pathogenic variants in the PACS1 gene. PACS1 is a trans-Golgi-membrane traffic regulator that directs protein cargo and several viral envelope proteins. It is upregulated during human embryonic brain development and has low expression after birth. So far, only 54 patients with SHMS have been reported. In this work, we report on seven new identified SHMS individuals with the classical c.607C > T: p.Arg206Trp PACS1 pathogenic variant and review clinical and molecular aspects of all the patients reported in the literature, providing a summary of clinical findings grouped as very frequent (≥75% of patients), frequent (50–74%), infrequent (26–49%) and rare (less than ≤25%).This work was possible thanks to the funding provided by the project “Proyecto Piloto para la mejora del diagnóstico genético en personas y familias afectadas o con sospecha de padecer enfermedades raras de base genética” of the Ministry of Health, under the grant BOCM-20181126-24 provided by the Consejería de Sanidad de la Comunidad de Madrid. Funding to J.P. and F.J.R. was partially provided by the group research grant DGA/FEDER B32_17R/B32_20R

A Novel Intragenic Duplication in the HDAC8 Gene Underlying a Case of Cornelia de Lange Syndrome

Cornelia de Lange syndrome; Genetic disorder; Intragenic duplicationSíndrome de Cornelia de Lange; Trastorno genético; Duplicación intragénicaSíndrome de Cornelia de Lange; Trastorn genètic; Duplicació intragènicaCornelia de Lange syndrome (CdLS) is a multisystemic genetic disorder characterized by distinctive facial features, growth retardation, and intellectual disability, as well as various systemic conditions. It is caused by genetic variants in genes related to the cohesin complex. Single-nucleotide variations are the best-known genetic cause of CdLS; however, copy number variants (CNVs) clearly underlie a substantial proportion of cases of the syndrome. The NIPBL gene was thought to be the locus within which clinically relevant CNVs contributed to CdLS. However, in the last few years, pathogenic CNVs have been identified in other genes such as HDAC8, RAD21, and SMC1A. Here, we studied an affected girl presenting with a classic CdLS phenotype heterozygous for a de novo ~32 kbp intragenic duplication affecting exon 10 of HDAC8. Molecular analyses revealed an alteration in the physiological splicing that included a 96 bp insertion between exons 9 and 10 of the main transcript of HDAC8. The aberrant transcript was predicted to generate a truncated protein whose accessibility to the active center was restricted, showing reduced ease of substrate entry into the mutated enzyme. Lastly, we conclude that the duplication is responsible for the patient’s phenotype, highlighting the contribution of CNVs as a molecular cause underlying CdLS.This work was supported by the Spanish Ministry of Health-ISCIII Fondo de Investigación Sanitaria (FIS) (Ref. PI19/01860, to F.J.R. and J.P.) and Diputación General de Aragón-FEDER: European Social Fund (Grupo de Referencia B32_17R/B32_20R, to J.P.). A.L.-P. is supported by a “Juan de la Cierva-Incorporación” postdoctoral grant from MICIU (Spanish Ministry of Science and Universities), M.G.-S. is supported by a Predoctoral Fellowship from the Diputación General de Aragón, and C.L.-C. is supported by a Predoctoral Fellowship from the MH-ISCIII. This work was also supported by Spanish government grants RTI2018-094434-B-I00 (MCIU/AEI/FEDER, UE) and DTS20-00024 (ISCIII) to P.G.-P., as well as funds from the European JPIAMR network “EPIC-Alliance” to P.G.-P. The computational support of the “Centro de Computación Científica CCC-UAM” is gratefully recognized. This work was also partially supported by Spanish Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias co-funded with ERDF funds, Grant No. FIS PI20/01767) to A.P. and by Spanish Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias co-funded with ERDF funds, Grant No. FIS PI18/000687 to E.F.T

Deep Molecular Characterization of Milder Spinal Muscular Atrophy Patients Carrying the c.859G>C Variant in SMN2

Next-generation sequencing; Phenotype–genotype correlations; Spinal muscular atrophySeqüenciació de nova generació; Correlacions fenotip-genotip; Atròfia muscular espinalSecuenciación de nueva generación; Correlaciones fenotipo-genotipo; Atrofia muscular espinalSpinal muscular atrophy (SMA) is a severe neuromuscular disorder caused by biallelic loss or pathogenic variants in the SMN1 gene. Copy number and modifier intragenic variants in SMN2, an almost identical paralog gene of SMN1, are known to influence the amount of complete SMN proteins. Therefore, SMN2 is considered the main phenotypic modifier of SMA, although genotype–phenotype correlation is not absolute. We present eleven unrelated SMA patients with milder phenotypes carrying the c.859G>C-positive modifier variant in SMN2. All were studied by a specific NGS method to allow a deep characterization of the entire SMN region. Analysis of two homozygous cases for the variant allowed us to identify a specific haplotype, Smn2-859C.1, in association with c.859G>C. Two other cases with the c.859G>C variant in their two SMN2 copies showed a second haplotype, Smn2-859C.2, in cis with Smn2-859C.1, assembling a more complex allele. We also identified a previously unreported variant in intron 2a exclusively linked to the Smn2-859C.1 haplotype (c.154-1141G>A), further suggesting that this region has been ancestrally conserved. The deep molecular characterization of SMN2 in our cohort highlights the importance of testing c.859G>C, as well as accurately assessing the SMN2 region in SMA patients to gain insight into the complex genotype–phenotype correlations and improve prognostic outcomes.This research was funded by grants from Biogen (ESP-SMG-17-11256), Roche, GaliciAME and Spanish Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias and co-funded with ERDF funds (grant no. FIS PI18/000687). A grant from Horizon 2020 IMI2 Screen4Care is acknowledged by E.B., and L.T., E.F.T., R.J., J.S., L.C.-C., F.M., E.B., and L.T. are members of the ERN NMD Network for Rare Diseases. E.F.T. is a member of the ERN ITHACA Network for Rare Diseases

Expanding the clinical and genetic spectra of primary immunodeficiency-related disorders with clinical exome sequencing: expected and unexpected findings

Inmunodeficiencias primarias; Secuenciación de próxima generación; Secuenciación clínica del exomaImmunodeficiències primàries; Seqüenciació de propera generació; Seqüenciació clínica d’exomesPrimary immunodeficiencies; Next generation sequencing; Clinical exome sequencingPrimary immunodeficiencies (PIDs) refer to a clinically, immunologically, and genetically heterogeneous group of over 350 disorders affecting development or function of the immune system. The increasing use of next-generation sequencing (NGS) technology has greatly facilitated identification of genetic defects in PID patients in daily clinical practice. Several NGS approaches are available, from the unbiased whole exome sequencing (WES) to specific gene panels. Here, we report on a 3-year experience with clinical exome sequencing (CES) for genetic diagnosis of PIDs. We used the TruSight One sequencing panel, which includes 4,813 disease-associated genes, in 61 unrelated patients (pediatric and adults). The analysis was done in 2 steps: first, we focused on a virtual PID panel and then, we expanded the analysis to the remaining genes. A molecular diagnosis was achieved in 19 (31%) patients: 12 (20%) with mutations in genes included in the virtual PID panel and 7 (11%) with mutations in other genes. These latter cases provided interesting and somewhat unexpected findings that expand the clinical and genetic spectra of PID-related disorders, and are useful to consider in the differential diagnosis. We also discuss 5 patients (8%) with incomplete genotypes or variants of uncertain significance. Finally, we address the limitations of CES exemplified by 7 patients (11%) with negative results on CES who were later diagnosed by other approaches (more specific PID panels, WES, and comparative genomic hybridization array). In summary, the genetic diagnosis rate using CES was 31% (including a description of 12 novel mutations), which rose to 42% after including diagnoses achieved by later use of other techniques. The description of patients with mutations in genes not included in the PID classification illustrates the heterogeneity and complexity of PID-related disorders.This study was funded by Instituto de Salud Carlos III, grants PI14/00405 and PI17/00660, cofinanced by the European Regional Development Fund (ERDF)