We identified biallelic mutations in NANS, the gene encoding the synthase for N-acetylneuraminic acid (NeuNAc; sialic acid), in nine individuals with infantile-onset severe developmental delay and skeletal dysplasia. Patient body fluids showed an elevation in N-acetyl-D-mannosamine levels, and patient-derived fibroblasts had reduced NANS activity and were unable to incorporate sialic acid precursors into sialylated glycoproteins. Knockdown of nansa in zebrafish embryos resulted in abnormal skeletal development, and exogenously added sialic acid partially rescued the skeletal phenotype. Thus, NANS-mediated synthesis of sialic acid is required for early brain development and skeletal growth. Normal sialylation of plasma proteins was observed in spite of NANS deficiency. Exploration of endogenous synthesis, nutritional absorption, and rescue pathways for sialic acid in different tissues and developmental phases is warranted to design therapeutic strategies to counteract NANS deficiency and to shed light on sialic acid metabolism and its implications for human nutrition. DOI: https://doi.org/10. 1038/ng.3578 Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-130493 Accepted Version Originally published at: van Karnebeek, Clara D M; Bonafé, Luisa; Wen, Xiao-Yan; Tarailo-Graovac, Maja; Balzano, Sara; RoyerBertrand, Beryl; Ashikov, Angel; Garavelli, Livia; Mammi, Isabella; Turolla, Licia; Breen, Catherine; Donnai, Dian; Cormier, Valerie; Heron, Delphine; Nishimura, Gen; Uchikawa, Shinichi; Campos-Xavier, Belinda; Rossi, Antonio; Hennet, Thierry; Brand-Arzamendi, Koroboshka; Rozmus, Jacob; Harshman, Keith; Stevenson, Brian J; Girardi, Enrico; Superti-Furga, Giulio; Dewan, Tammie; Collingridge, Alissa; Halparin, Jessie; Ross, Colin J; Van Allen, Margot I;et al (2016). NANS-mediated synthesis of sialic acid is required for brain and skeletal development. Nature Genetics, 48 (7) insights into the molecular basis of neurocognitive impairment allows for the development and 89 application of targeted therapeutic strategies 5 . Although less frequent than IDD, genetic disorders 90 affecting skeletal development and growth (commonly called the "skeletal dysplasias") are a 91 group of over 500 distinct disorders 6 . Studying their molecular basis has provided precious 92 insights into the many factors necessary for skeletal development, ranging from minerals and 93 structural molecules to enzymes, to signaling molecules and transcription factors 6,7 . We report 94here a genetic disorder presenting with a combination of severe IDD with skeletal dysplasia and 95 short stature. Our data show that its pathogenic basis is an inborn error of metabolism that 96 affects the endogenous synthesis of N-acetyl neuraminic acid (NeuNAc; sialic acid). Exploration 97 of the biochemical and molecular features of this disorder provides new information on the role 98 of sialic acid in the development of brain and bone. 99 100 RESULTS 101 Clinical and radiographic phenotype of N...

BackgroundKabuki syndrome (Niikawa-Kuroki syndrome) is a rare, multiple congenital anomalies/mental retardation syndrome characterized by a peculiar face, short stature, skeletal, visceral and dermatoglyphic abnormalities, cardiac anomalies, and immunological defects. Recently mutations in the histone methyl transferase MLL2 gene have been identified as its underlying cause.MethodsGenomic DNAs were extracted from 62 index patients clinically diagnosed as affected by Kabuki syndrome. Sanger sequencing was performed to analyze the whole coding region of the MLL2 gene including intron-exon junctions. The putative causal and possible functional effect of each nucleotide variant identified was estimated by in silico prediction tools.ResultsWe identified 45 patients with MLL2 nucleotide variants. 38 out of the 42 variants were never described before. Consistently with previous reports, the majority are nonsense or frameshift mutations predicted to generate a truncated polypeptide. We also identified 3 indel, 7 missense and 3 splice site.ConclusionsThis study emphasizes the relevance of mutational screening of the MLL2 gene among patients diagnosed with Kabuki syndrome. The identification of a large spectrum of MLL2 mutations possibly offers the opportunity to improve the actual knowledge on the clinical basis of this multiple congenital anomalies/mental retardation syndrome, design functional studies to understand the molecular mechanisms underlying this disease, establish genotype-phenotype correlations and improve clinical management.

Methods of classical segregation analysis were applied to a sample of 129 sibships with one or more individuals affected by neurofibromatosis-1 (NF-1). The sample consists only of subjects with NF-1; all the probands had been referred for genetic counselling because of café-au-lait spots, and a diagnostic protocol was invariably applied. No deviation from the segregation ratio expected for a fully penetrant Mendelian dominant gene was observed. A maximum likelihood estimate of the proportion of sporadic cases was obtained, and the mutation rate was estimated to be 6.5 x 10(-5) gametes per generation (95% CI 5.0-8.1).

Intellectual disability (ID) and autism spectrum disorder (ASD) are clinically and genetically heterogeneous diseases. Recent whole exome sequencing studies indicated that genes associated with different neurological diseases are shared across disorders and converge on common functional pathways. Using the Ion Torrent platform, we developed a low‐cost next‐generation sequencing gene panel that has been transferred into clinical practice, replacing single disease‐gene analyses for the early diagnosis of individuals with ID/ASD. The gene panel was designed using an innovative in silico approach based on disease networks and mining data from public resources to score disease‐gene associations. We analyzed 150 unrelated individuals with ID and/or ASD and a confident diagnosis has been reached in 26 cases (17%). Likely pathogenic mutations have been identified in another 15 patients, reaching a total diagnostic yield of 27%. Our data also support the pathogenic role of genes recently proposed to be involved in ASD. Although many of the identified variants need further investigation to be considered disease‐causing, our results indicate the efficiency of the targeted gene panel on the identification of novel and rare variants in patients with ID and ASD.

This report concerns 2 unrelated patients with apparent CHARGE association and a chromosome abnormality, resulting from different unbalanced familial translocations involving chromosomes 2 and 18 in one family, and chromosomes 3 and 22 in the other. Although the identification of two different chromosome abnormalities might be due to chance, the observation of a long arm deletion of chromosome 22 in patients 2 and of the frequent coexistence of CHARGE association and DiGeorge anomaly raise the possibility of a contiguous gene syndrome in at least some CHARGE cases.