Abstract Background Short tandem repeats (STRs) are widely distributed across the human genome and are associated with numerous neurological disorders. However, the extent that STRs contribute to disease is likely under-estimated because of the challenges calling these variants in short read next generation sequencing data. Several computational tools have been developed for STR variant calling, but none fully address all of the complexities associated with this variant class. Results Here we introduce LUSTR which is designed to address some of the challenges associated with STR variant calling by enabling more flexibility in defining STR loci, allowing for customizable modules to tailor analyses, and expanding the capability to call somatic and multiallelic STR variants. LUSTR is a user-friendly and easily customizable tool for targeted or unbiased genome-wide STR variant screening that can use either predefined or novel genome builds. Using both simulated and real data sets, we demonstrated that LUSTR accurately infers germline and somatic STR expansions in individuals with and without diseases. Conclusions LUSTR offers a powerful and user-friendly approach that allows for the identification of STR variants and can facilitate more comprehensive studies evaluating the role of pathogenic STR variants across human diseases.
Treatment for type 1 Gaucher disease (GD1) decreases morbidity from hematological cytopenias, hepatosplenomegaly and bone complications. Consequently, untreated symptomatic patients for study of late outcomes are hard to find. We identified 184 untreated GD1 patients (67.4% Ashkenazi; splenectomy 51.1%) who died between 1950 and 2010. Here, we report confirmed causes of death for these patients compared with the overall US population. Median age of death 66years (2-97years); causes of death (COD) with a high proportional mortality rate (PMR) included malignancies (PMR 1.57), suicide/drug overdose (PMR 3.86), liver disease (PMR 4.76) and septicemia (PMR 9.22). PMRs for CNS/gastrointestinal bleeding, pulmonary hypertension, post-splenectomy complications and Parkinsonism were also increased. PMR for heart disease (0.33) was significantly decreased. Average age at death was normal for heart disease, septicemia, suicide, and malignancies but younger for liver disease and Parkinsonism. COD more prevalent in splenectomy patients included liver disease, septicemia, pulmonary hypertension and GI bleeding. With timely diagnosis, improved risk assessment and obsolescence of splenectomy, GD1-associated malignancies, liver disease, septicemia, pulmonary hypertension, suicide and drug dependency may decrease with early institution of appropriate treatment. Our population of untreated patients is a valuable historical control for studies of the effect of GD1 treatment on premature mortality.
Diphthamide is a post-translationally modified histidine essential for messenger RNA translation and ribosomal protein synthesis. We present evidence for DPH5 as a novel cause of embryonic lethality and profound neurodevelopmental delays (NDDs).Molecular testing was performed using exome or genome sequencing. A targeted Dph5 knockin mouse (C57BL/6Ncrl-Dph5em1Mbp/Mmucd) was created for a DPH5 p.His260Arg homozygous variant identified in 1 family. Adenosine diphosphate-ribosylation assays in DPH5-knockout human and yeast cells and in silico modeling were performed for the identified DPH5 potential pathogenic variants.DPH5 variants p.His260Arg (homozygous), p.Asn110Ser and p.Arg207Ter (heterozygous), and p.Asn174LysfsTer10 (homozygous) were identified in 3 unrelated families with distinct overlapping craniofacial features, profound NDDs, multisystem abnormalities, and miscarriages. Dph5 p.His260Arg homozygous knockin was embryonically lethal with only 1 subviable mouse exhibiting impaired growth, craniofacial dysmorphology, and multisystem dysfunction recapitulating the human phenotype. Adenosine diphosphate-ribosylation assays showed absent to decreased function in DPH5-knockout human and yeast cells. In silico modeling of the variants showed altered DPH5 structure and disruption of its interaction with eEF2.We provide strong clinical, biochemical, and functional evidence for DPH5 as a novel cause of embryonic lethality or profound NDDs with multisystem involvement and expand diphthamide-deficiency syndromes and ribosomopathies.
A small supernumerary marker chromosome (SMC) was observed in a girl with severe developmental delay. Her dysmorphism included prominent forehead, hypertelorism, down-slanting palpebral fissures, low-set/large ears, and flat nasal bridge with anteverted nares. This case also presented hypotonia, hypermobility of joints, congenital heart defect, umbilical hernia, failure to thrive, and seizures. The SMC originated from the distal region of Xp as identified by FISH with multiple DNA probes. Staining with antibodies to Centromere Protein C (CENP-C) demonstrated a neocentromere, while FISH with an α-satellite DNA probe showed no hybridization to the SMC. A karyotype was described as 47,XX,+neo(X)(pter→p22.31::p22.31→pter), indicating a partial tetrasomy of Xp22.31→pter. This karyotype represents a functional trisomy for Xp22.31→pter and a functional tetrasomy for the pseudoautosomal region given that there is no X-inactivation center in the marker chromosome. The SMC was further characterized by microarray-based comparative genomic hybridization (array CGH) as a duplicated DNA fragment of approximately 13 megabase pairs containing about 100 genes. We have described here a new neocentromere with discussion of its clinical significance.
Pompe disease (PD) is an autosomal recessive condition caused by GAA gene variants that affects lysosomal enzyme production, acid alpha-glucosidase (GAA), leading to glycogen buildup in the organelle. There are two distinct presentations of the disease: Infantile Onset (IOPD) with severe symptoms in infancy and Late Onset (LOPD) with progressive muscle affection and breathing difficulties at any age. Several countries and US states have included PD into their Newborn Screening (NBS) programs since the advent of treatments that decrease disease morbidity and mortality.
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