Multiple sulfatase deficiency (MSD) is an ultra-rare neurodegenerative disorder caused by pathogenic variants in SUMF1. This gene encodes formylglycine-generating enzyme (FGE), a protein required for sulfatase activation. The clinical course of MSD results from additive effect of each sulfatase deficiency, including metachromatic leukodystrophy (MLD), several mucopolysaccharidoses (MPS II, IIIA, IIID, IIIE, IVA, VI), chondrodysplasia punctata, and X-linked ichthyosis. While it is known that affected individuals demonstrate a complex and severe phenotype, the genotype-phenotype relationship and detailed clinical course is unknown. We report on 35 cases enrolled in our retrospective natural history study, n = 32 with detailed histories. Neurologic function was longitudinally assessed with retrospective scales. Biochemical and computational modeling of novel SUMF1 variants was performed. Genotypes were classified based on predicted functional change, and each individual was assigned a genotype severity score. The median age at symptom onset was 0.25 years; median age at diagnosis was 2.7 years; and median age at death was 13 years. All individuals demonstrated developmental delay, and only a subset of individuals attained ambulation and verbal communication. All subjects experienced an accumulating systemic symptom burden.

Purpose McArdle disease is one of the most common glycogen storage disorders. Although the exact prevalence is not known, it has been estimated to be 1 in 100,000 patients in the United States. More than 100 mutations in PYGM have been associated with this disorder. McArdle disease has significant clinical variability with some patients presenting with severe muscle pain and weakness while others have only mild, exercise-related symptoms. Methods Next-Generation sequencing data allow estimation of disease prevalence with minimal ascertainment bias. We analyzed gene frequencies in two cohorts of patients from exome sequencing results. We categorized variants into three groups: a curated set of published mutations, variants of uncertain significance, and likely benign variants. Results An initial estimate based on the frequency of six common mutations predicts a disease prevalence of 1/7,650 (95% CI 1/5,362 to 1/11,108), which greatly deviates from published estimates. A second method using the two most common mutations predicts a prevalence of 1/42,355 (95% CI 1/24,536 - 1/76,310) in Caucasians. Conclusions These results suggest that the currently accepted prevalence of McArdle disease is an underestimate and that some of the currently considered pathogenic variants are likely benign.

Multiple sulfatase deficiency (MSD) is an ultra-rare neurodegenerative disorder that results in defective sulfatase post-translational modification. Sulfatases in the body are activated by a unique protein, formylglycine-generating enzyme (FGE) that is encoded by SUMF1. When FGE is absent or insufficient, all 17 known human sulfatases are affected, including the enzymes associated with metachromatic leukodystrophy (MLD), several mucopolysaccharidoses (MPS II, IIIA, IIID, IVA, VI), chondrodysplasia punctata, and X-linked ichthyosis. As such, individuals demonstrate a complex and severe clinical phenotype that has not been fully characterized to date. In this report, we describe two individuals with distinct clinical presentations of MSD. Also, we detail a comprehensive systems-based approach to the management of individuals with MSD, from the initial diagnostic evaluation to unique multisystem issues and potential management options. As there have been no natural history studies to date, the recommendations within this report are based on published studies and consensus opinion and underscore the need for future research on evidence-based outcomes to improve management of children with MSD.

for the MilSeq Project BACKGROUND: Genotyping has expanded the number red blood cell (RBC) and platelet (PLT) antigens that can readily be typed, but often represents an additional testing cost. The analysis of existing genomic data offers a cost-effective approach. We recently developed automated software (bloodTyper) for determination of RBC and PLT antigens from whole genome sequencing. Here we extend the algorithm to whole exome sequencing (WES). STUDY DESIGN AND METHODS: Whole exomesequencing was performed on samples from 75 individuals. WES-based bloodTyper RBC and PLT typing was compared to conventional polymerase chain reaction (PCR) RHD zygosity testing and serologic and single-nucleotide polymorphism (SNP) typing for 38 RBC antigens in 12 systems (17 serologic and 35 SNPs) and 22 PLT antigens (22 SNPs). Samples from the first 20 individuals were used to modify bloodTyper to interpret WES followed by blinded typing of 55 samples. RESULTS:Over the first 20 samples, discordances were noted for C, M, and N antigens, which were due to WES-specific biases. After modification, bloodTyper was 100% accurate on blinded evaluation of the last 55 samples and outperformed both serologic (99.67% accurate) and SNP typing (99.97% accurate) reflected by two Fy b and one N serologic typing errors and one undetected SNP encoding a Jk null phenotype. RHD zygosity testing by bloodTyper was 100% concordant with a combination of hybrid Rhesus box PCR and PCRrestriction fragment length polymorphism for all samples. CONCLUSION:The automated bloodTyper software was modified for WES biases to allow for accurate RBC and PLT antigen typing. Such analysis could become a routing part of future WES efforts.

Genetics and Genomic medicine in Colombia.

The announcement of the Precision Medicine Initiative was an important step towards establishing the use of genomic information as part of the wider practice of medicine. The US military has been exploring the role that genomic information will have in health care for service members (SMs) and its integration into the continuum of military medicine. An important part of the process is establishing robust protections to protect SMs from genetic discrimination in the era of exome/genome sequencing.

This is a foreword on the life and work of one of the greatest minds of the 20th century, the father of modern genetics, Johann Gregor Mendel.

Taken as a group, genetic disorders affect a significant proportion of the population. Historically thought of as pediatric disorders, inborn errors of metabolism (IEM) are becoming increasingly relevant to the adult clinical provider; given the improvements in screening, diagnosis and management, an increasing number of children with IEM's are able to transition adulthood. Currently available data suggests that adult-medicine clinical providers are ill-prepared to appropriately care for this population. Although practical management and transition guidelines exist for a minority of disorders, there is a significant lack of guidance for the great majority of conditions. Based on our review of the relevant literature, we set out to provide practical recommendations to assist in the transition from adolescence to adulthood, with an emphasis on patients with an inborn error of metabolism.