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Autosomal recessive Cohen syndrome is a neurodevelopmental disorder characterized by postnatal microcephaly, intellectual disability, and a typical facial gestalt. Genetic variants in VPS13B have been found to cause Cohen syndrome, but have also been linked to autism, retinal disease, primary immunodeficiency, and short stature. While it is well established that loss-of-function mutations of VPS13B cause Cohen syndrome, the relevance of missense variants for the pathomechanism remains unexplained. Here, we investigate their pathogenic effect through a systematic re-evaluation of clinical patient information, comprehensive in silico predictions, and in vitro testing of previously published missense variants. In vitro analysis of 10 subcloned VPS13B missense variants resulted in full-length proteins after transient overexpression. 6/10 VPS13B missense variants show reduced accumulation at the Golgi complex in the steady state. The overexpression of these 6/10 VPS13B missense variants did not rescue the Golgi fragmentation after the RNAi-mediated depletion of endogenous VPS13B . These results thus validate 6/10 missense variants as likely pathogenic according to the classification of the American College of Medical Genetics through the integration of clinical, genetic, in silico , and experimental data. In summary, we state that exact variant classification should be the first step towards elucidating the pathomechanisms of genetically inherited neuronal diseases.

Cohen syndrome (CS) is an early-onset pediatric neurodevelopmental disorder characterized by postnatal microcephaly and intellectual disability. An accurate diagnosis for individuals with CS is crucial, particularly for their caretakers and future prospects. CS is predominantly caused by rare homozygous or compound heterozygous pathogenic variants in the vacuolar protein sorting-associated 13B ( ) gene, which disrupt protein translation and lead to a loss of function (LoF) of the encoded VPS13B protein. The widespread incorporation of next-generation sequencing approaches in genetic diagnostics increases the number of individuals carrying mutant alleles. At the same time, it increases the detection of variants of unknown clinical significance, necessitating further functional pathogenicity validation. In this study, we present a family with two CS patients. Within this family, four rare variants were detected: c.710G > C, p.Arg237Pro; c.6804delT, p.Phe2268Leufs*24; c.7304C > T, p.Ala2435Val; and c.10302T > A, p.Tyr3434*. These variants challenge the interpretation of their disease-causing role. Specifically, the variants c.6804delT, p.Phe2268Leufs*24 and c.710G > C, p.Arg237Pro were detected in trans configuration and are considered to be causing CS genetically. The functional characterization of the missense variant c.710G > C, p.Arg237Pro shows diminished localization at the Golgi complex, highlighting its clinical relevance and supporting its classification by the American College of Medical Genetics and Genomics (ACMG) as likely pathogenic, class 4. Overall, we emphasize the need for combining genetic and functional testing of VPS13B missense variants to ensure accurate molecular diagnosis and personalized medical care for CS patients.

Stefan Mundlos and colleagues report the identification of mutations in SCYL1BP1 in families with gerodermia osteodysplastica, a disorder characterized by wrinkly skin and osteoporosis. SCYL1BP1 localizes to the Golgi apparatus and interacts with Rab6. Gerodermia osteodysplastica is an autosomal recessive disorder characterized by wrinkly skin and osteoporosis. Here we demonstrate that gerodermia osteodysplastica is caused by loss-of-function mutations in SCYL1BP1 , which is highly expressed in skin and osteoblasts. The protein localizes to the Golgi apparatus and interacts with Rab6, identifying SCYL1BP1 as a golgin. These results associate abnormalities of the secretory pathway with age-related changes in connective tissues.

Bone fragility due to osteopenia, osteoporosis or debilitating focal skeletal dysplasias is a frequent observation in the Mendelian disease Neurofibromatosis type 1 (NF1). To determine the mechanisms underlying bone fragility in NF1 we analyzed two conditional mouse models, Nf1Prx1 (limb knock-out) and Nf1Col1 (osteoblast specific knock-out), as well as cortical bone samples from individuals with NF1. We examined mouse bone tissue with micro-computed tomography, qualitative and quantitative histology, mechanical tensile analysis, small-angle X-ray scattering (SAXS), energy dispersive X-ray spectroscopy (EDX), and scanning acoustic microscopy (SAM). In cortical bone of Nf1Prx1 mice we detected ectopic blood vessels that were associated with diaphyseal mineralization defects. Defective mineral binding in the proximity of blood vessels was most likely due to impaired bone collagen formation, as these areas were completely devoid of acidic matrix proteins and contained thin collagen fibers. Additionally, we found significantly reduced mechanical strength of the bone material, which was partially caused by increased osteocyte volume. Consistent with these observations, bone samples from individuals with NF1 and tibial dysplasia showed increased osteocyte lacuna volume. Reduced mechanical properties were associated with diminished matrix stiffness, as determined by SAM. In line with these observations, bone tissue from individuals with NF1 and tibial dysplasia showed heterogeneous mineralization and reduced collagen fiber thickness and packaging. Collectively, the data indicate that bone fragility in NF1 tibial dysplasia is partly due to an increased osteocyte-related micro-porosity, hypomineralization, a generalized defect of organic matrix formation, exacerbated in the regions of tensional and bending force integration, and finally persistence of ectopic blood vessels associated with localized macro-porotic bone lesions.

Background Floating-Harbor syndrome is a rare autosomal dominant short stature syndrome with retarded speech development, intellectual disability and dysmorphic facial features. Recently dominant mutations almost exclusively located in exon 34 of the Snf2-related CREBBP activator protein gene were identified to cause FHS. Methods Here we report the genetic analysis of 5 patients fulfilling the diagnostic criteria of FHS obtained by Sanger sequencing. All of them presented with short stature, speech delay as well as psychomotor delay and typical facial dysmorphism. Three patients showed a good response to growth hormone treatment. Results Two patients demonstrate novel, heterozygous de novo frameshift mutations in exon 34 (c.7396delA and c.7218dupT) leading to premature stop mutations in SRCAP (p.Val2466Tyrfs*9 and p.Gln2407Serfs*36, respectively). In two further patients we found already known SRCAP mutations in exon 34, c.7330C > T and c.7303C > T, respectively, which also lead to premature stop codons: p.Arg2444* and p.Arg2435*. In one patient, we identified a novel de novo stop mutation in exon 33 (c.6985C > T, p.Arg2329*) demonstrating that not all FHS cases are caused by mutations in exon 34 of SRCAP . Conclusions Our data confirm a mutational hot spot in the final exon of SRCAP in the majority of FHS patients but also show that exon 33 of this gene can be affected.

Cranio-osteoarthropathy, clinically classified as a variant of primary hypertrophic osteoarthropathy, is a very rare autosomal-recessive condition characterized by delayed closure of the cranial sutures and fontanels, digital clubbing, arthropathy, and periostosis. Recently, mutations in the gene HPGD , which encodes the NAD + -dependent 15-hydroxyprostaglandin dehydrogenase, were reported in four families affected with primary hypertrophic osteoarthropathy and one family with autosomal-recessive isolated nail clubbing. We report the clinical and molecular findings in four patients from two families affected with cranio-osteoarthropathy and one family with isolated, autosomal dominant digital clubbing. Genome-wide homozygosity mapping identified a locus for cranio-osteoarthropathy harboring the HPGD gene in one affected family. We detected two novel homozygous mutations in HPGD in these families: a missense mutation affecting the NAD + binding motif and a frameshift mutation. The clinical presentation in our patients was variable. Digital clubbing and hyperhidrosis were present in all cases. Delayed closure of the cranial sutures and fontanels, periostosis, and arthropathy were not consistent clinical features. No HPGD mutation was detected in a familial case of autosomal dominant isolated digital clubbing. The failure to identify any mutation in a family with an autosomal dominant type of isolated digital clubbing suggests that HPGD is not the major gene for this condition.