Cold Spring Harbor Molecular Case Studies最新文献

Cobalamin C disease is the most common complementation class of cobalamin disorders. Here, we present a case of a 14-yr-old male with early-onset cblC disease and autism spectrum disorder (ASD) admitted to our inpatient medical service for behavioral decompensation. We use this case to highlight key aspects of the neurodevelopmental and neuropsychiatric disorders associated with cblC disease. By incorporating a comprehensive review of existing literature, we highlight salient domains of psychological impairment in cblC disease, discuss the full range of neuropsychiatric presentations, and review clinical management implications unique to cblC disease.

Closed spinal dysraphism (SD) is a type of neural tube defect originating during early embryonic development whereby the neural tissue of the spinal defect remains covered by skin, often coinciding with markers of cutaneous stigmata. It is hypothesized that these events are caused by multifactorial processes, including genetic and environmental causes. We present an infant with a unique congenital midline lesion associated with a closed SD. Through comprehensive molecular profiling of the intraspinal lesion and contiguous skin lesion, an internal tandem duplication (ITD) of the kinase domain of the fibroblast growth factor receptor 1 (FGFR1) gene was found. This ITD variant is somatic mosaic in nature as supported by a diminished variant allele frequency in the lesional tissue and by its absence in peripheral blood. FGFR1 ITD results in constitutive activation of the receptor tyrosine kinase to promote cell growth, differentiation, and survival through RAS/MAPK signaling. Identification of FGFR1 ITD outside of central nervous system tumors is exceedingly rare, and this report broadens the phenotypic spectrum of somatic mosaic FGFR1-related disease.

Microvillus inclusion disease (MVID) is a rare autosomal recessive condition characterized by a lack of microvilli on the surface of enterocytes, resulting in severe, life-threatening diarrhea that could lead to mortality within the first year of life. We identify two unrelated families, each with one child presenting with severe MVID from birth. Using trio whole-exome sequencing, we observed that the two families share a novel nonsense variant (Glu1589*) in the MYO5B gene, a type Vb myosin motor protein in which rare damaging mutations were previously described to cause MVID. This founder mutation was very rare in public databases and is likely specific to patients of Syrian ancestry. We present a detailed account of both patients' clinical histories to fully characterize the effect of this variant and expand the genotype-phenotype databases for MVID patients from the Middle East.

An SLC30A9-associated cerebrorenal syndrome was first reported in consanguineous Bedouin kindred by Perez et al. in 2017. Although the function of the gene has not yet been fully elucidated, it may be implicated in Wnt signaling and nuclear regulation, as well as in cell and mitochondrial zinc regulation. In this research report, we present a female proband with two distinct, inherited autosomal recessive loss-of-function SLC30A9 variants from unrelated parents. To our knowledge, this is the first reported case of a possible SLC30A9-associated cerebrorenal syndrome in a nonconsanguineous family. Furthermore, a limited statistical analysis was conducted to identify possible allele frequency differences between populations. Our findings provide further support for an SLC30A9-associated cerebrorenal syndrome and may help clarify the gene's function through its possible disease association.

Rare neurogenetic disorders are collectively common, affecting 3% of the population, and often manifest with complex multiorgan comorbidity. With advances in genetic, -omics, and computational analysis, more children can be diagnosed and at an earlier age. Innovations in translational research facilitate the identification of treatment targets and development of disease-modifying drugs such as gene therapy, nutraceuticals, and drug repurposing. This increasingly allows targeted therapy to prevent the often devastating manifestations of rare neurogenetic disorders. In this perspective, successes in diagnosis, prevention, and treatment are discussed with a focus on inherited disorders of metabolism. Barriers for the identification, development, and implementation of rare disease-specific therapies are discussed. New methodologies, care networks, and collaborative frameworks are proposed to optimize the potential of personalized genomic medicine to decrease morbidity and improve lives of these vulnerable patients.

Noncoding and synonymous coding variants that exert their effects via alternative splicing are increasingly recognized as an important category of disease-causing variants. In this report, we describe two siblings who presented with hypotonia, profound developmental delays, and seizures. Brain magnetic resonance imaging (MRI) in the proband at 5 yr showed diffuse cerebral and cerebellar white matter volume loss. Both siblings later developed ventilator-dependent respiratory insufficiency and scoliosis and are currently nonverbal and nonambulatory. Extensive molecular testing including oligo array and clinical exome sequencing was nondiagnostic. Research genome sequencing under an institutional review board (IRB)-approved study protocol revealed that both affected children were compound-heterozygous for variants in the SEPSECS gene. One variant was an initiator codon change (c.1A > T) that disrupted protein translation, consistent with the observation that most disease-causing variants are loss-of-function changes. The other variant was a coding change (c.846G > A) that was predicted to be synonymous but had been demonstrated to disrupt mRNA splicing in a minigene assay. The SEPSECS gene encodes O-phosphoseryl-tRNA(Sec) selenium transferase, an enzyme that participates in the biosynthesis and transport of selenoproteins in the body. Variations in SEPSECS cause autosomal recessive pontocerebellar hypoplasia type 2D (PCHT 2D; OMIM #613811), a neurodegenerative condition characterized by progressive cerebrocerebellar atrophy, microcephaly, and epileptic encephalopathy. The identification of biallelic pathogenic variants in this family-one of which was a synonymous change not identified by prior clinical testing-not only ended the diagnostic odyssey for this family but also highlights the contribution of occult pathogenic variants that may not be recognized by standard genetic testing methodologies.

Rod-cone dystrophy (RCD), also known as retinitis pigmentosa, is an inherited condition leading to vision loss, affecting 1 in 3500 people. More than 270 genes are known to be implicated in the inherited retinal degenerations (IRDs), yet genetic diagnosis for ∼30% of IRD of patients remains elusive despite advances in sequencing technologies. The goal of this study was to determine the genetic causality in a family with RCD. Family members were given a full ophthalmic exam at the Retinal Service at Massachusetts Eye and Ear and consented to genetic testing. Whole-exome sequencing (WES) was performed and variants of interest were Sanger-validated. Functional assays were conducted in zebrafish along with splicing assays in relevant cell lines to determine the impact on retinal function. WES identified variants in two potential candidate genes that segregated with disease: GNL3 (G Protein Nucleolar 3) c.1187 + 3A > C and c.1568-8C > A; and PDE4DIP (Phosphodiester 4D Interacting Protein) c.3868G > A (p.Glu1290Lys) and c.4603G > A (p.Ala1535Thr). Both genes were promising candidates based on their retinal involvement (development and interactions with IRD-associated proteins); however, the functional assays did not validate either gene. Subsequent WES reanalysis with an updated bioinformatics pipeline and widened search parameters led to the detection of a 94-bp duplication in PRPF31 (pre-mRNA Processing Factor 31) c.73_266dup (p.Asp56GlyfsTer33) as the causal variant. Our study demonstrates the importance of thorough functional characterization of new disease candidate genes and the value of reanalyzing next-generation sequencing sequence data, which in our case led to identification of a hidden pathogenic variant in a known IRD gene.

McArdle disease is a debilitating glycogen storage disease with typical onset in childhood. Here, we describe a former competitive athlete with early adult-onset McArdle disease and a septuagenarian with a history of exercise intolerance since adolescence who was evaluated for proximal muscle weakness. Exome sequencing identified biallelic variants in the PYGM gene for both cases. The former athlete has the common, well-known pathogenic variant p.(Arg50Ter) in trans with a novel missense variant, p.(Asp694Glu). The second individual has a previously described homozygous missense variant, p.(Arg771Gln). Here, we describe the clinical course, enzyme-testing results using muscle tissue, and molecular findings for the individuals and add to the knowledge of the genotypic spectrum of this disorder.