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BackgroundSchaaf-Yang syndrome (SYS) is caused by truncating mutations inMAGEL2, mapping to the Prader-Willi region (15q11-q13), with an observed phenotype partially overlapping that of Prader-Willi syndrome. MAGEL2 plays a role in retrograde transport and protein recycling regulation. Our aim is to contribute to the characterisation of SYS pathophysiology at clinical, genetic and molecular levels.MethodsWe performed an extensive phenotypic and mutational revision of previously reported patients with SYS. We analysed the secretion levels of amyloid-β 1–40 peptide (Aβ1-40) and performed targeted metabolomic and transcriptomic profiles in fibroblasts of patients with SYS (n=7) compared with controls (n=11). We also transfected cell lines with vectors encoding wild-type (WT) or mutated MAGEL2 to assess stability and subcellular localisation of the truncated protein.ResultsFunctional studies show significantly decreased levels of secreted Aβ1-40and intracellular glutamine in SYS fibroblasts compared with WT. We also identified 132 differentially expressed genes, including non-coding RNAs (ncRNAs) such asHOTAIR, and many of them related to developmental processes and mitotic mechanisms. The truncated form of MAGEL2 displayed a stability similar to the WT but it was significantly switched to the nucleus, compared with a mainly cytoplasmic distribution of the WT MAGEL2. Based on the updated knowledge, we offer guidelines for the clinical management of patients with SYS.ConclusionA truncated MAGEL2 protein is stable and localises mainly in the nucleus, where it might exert a pathogenic neomorphic effect. Aβ1-40secretion levels andHOTAIRmRNA levels might be promising biomarkers for SYS. Our findings may improve SYS understanding and clinical management.

BackgroundSchaaf-Yang syndrome (SYS) is caused by truncating mutations in MAGEL2, mapping to the Prader-Willi region (15q11-q13), with an observed phenotype partially overlapping that of Prader-Willi syndrome. MAGEL2 plays a role in retrograde transport and protein recycling regulation. Our aim is to contribute to the characterization of SYS pathophysiology at clinical, genetic and molecular levels.MethodsWe performed an extensive phenotypic and mutational revision of previously reported SYS patients. We analysed the secretion levels of amyloid-β 1-40 peptide (Aβ1-40), and performed targeted metabolomic and transcriptomic profiles in SYS patients’ fibroblasts (n=7) compared to controls (n=11). We also transfected cell lines with vectors encoding wild-type (WT) or truncated MAGEL2 to assess stability and subcellular localization of the truncated protein.ResultsFunctional studies show significantly decreased levels of secreted Aβ1-40 and intracellular glutamine in SYS fibroblasts compared to wild-type. We also identified 132 differentially expressed genes, including ncRNAs such as HOTAIR, many of them related to developmental processes and mitotic mechanisms. The truncated form of MAGEL2 displayed a stability similar to the wild-type but it was significantly switched to the nucleus, compared to a mainly cytoplasmic distribution of the wild-type MAGEL2. Based on updated knowledge we offer guidelines for clinical management of SYS patients.ConclusionA truncated MAGEL2 protein is stable and localises mainly in the nucleus, where it might exert a pathogenic gain of function effect. Aβ1-40 secretion levels and HOTAIR mRNA levels might be promising biomarkers for SYS. Our findings may improve SYS understanding and clinical management.Key MessagesMAGEL2 truncating mutations cause Schaaf-Yang syndrome (SYS) but the functional effects of the truncated MAGEL2 protein have been poorly defined. By expressing truncated MAGEL2 in cell lines, we now know that a truncated version of the protein is retained in the nucleus, thus exerting a gain-of-function behaviour in addition to the loss of some of its main functions. Patients’ fibroblasts show reduced levels of excreted amyloid beta 1-40 and intracellular glutamine as well as an altered transcriptomic profile, including overexpression of the major regulator HOTAIR. Based on a comprehensive review of genetic and clinical aspects of all reported cases, families and physicians will benefit from the Clinical Management Recommendations that we provide here.

We present a Turkish family with two cousins (OC15 and OC15b) affected with syndromic developmental delay, microcephaly, and trigonocephaly but with some phenotypic traits distinct between them. OC15 showed asymmetrical skeletal defects and syndactyly, while OC15b presented with a more severe microcephaly and semilobal holoprosencephaly. All four progenitors were related and OC15 parents were consanguineous. Whole Exome Sequencing (WES) analysis was performed on patient OC15 as a singleton and on the OC15b trio. Selected variants were validated by Sanger sequencing. We did not identify any shared variant that could be associated with the disease. Instead, each patient presented a de novo heterozygous variant in a different gene. OC15 carried a nonsense mutation (p.Arg95*) in PORCN, which is a gene responsible for Goltz-Gorlin syndrome, while OC15b carried an indel mutation in ZIC2 leading to the substitution of three residues by a proline (p.His404_Ser406delinsPro). Autosomal dominant mutations in ZIC2 have been associated with holoprosencephaly 5. Both variants are absent in the general population and are predicted to be pathogenic. These two de novo heterozygous variants identified in the two patients seem to explain the major phenotypic alterations of each particular case, instead of a homozygous variant that would be expected by the underlying consanguinity. Funding was from the Spanish Ministerio de Ciencia e Innovación (SAF2016-75946R), CIBERER (ACCI2018-15), Associació Síndrome Opitz C. Departament de Salut de la Generalitat de Catalunya, PERIS SLT002/16/00174, URD-Cat (Implementació de la Medicina Personalitzada basada en la Genòmica en Malalties Minoritàries Neurològiques no Diagnosticades), 2017–2019