Molecular Genetics & Genomic Medicine最新文献

Background: Neuron navigator 3 (NAV3) is characterized as one of the neuron navigator family (NAV1, NAV2, NAV3) proteins predominantly expressed in the nervous system. The NAV3-encoded protein comprises a conserved AAA and coiled-coil domains characteristic of ATPases, which are associated with different cellular activities.

Methods: We describe a Saudi proband presenting a complex recessive neurodevelopmental disorder (NDD). Whole exome sequencing (WES) followed by Sanger sequencing, 3D protein modeling and RT-qPCR was performed.

Results: WES revealed a bi-allelic frameshift variant (c.2604_2605delAG; p.Val870SerfsTer12) in exon 12 of the NAV3 gene. Furthermore, RT-qPCR revealed a significant decrease in the NAV3 mRNA expression in the patient sample, and 3D protein modeling revealed disruption of the overall secondary structure.

Conclusion: For the time, we associate a bi-allelic variant in the NAV3 gene causing NDD in humans.

Background: Albinism is a heterogeneous condition in which patients present complete absence, reduction, or normal pigmentation in skin, hair and eyes in addition to ocular defects. One of the heterogeneous forms of albinism is observed in Hermansky-Pudlak syndrome (HPS) patients. HPS is characterized by albinism and hemorrhagic diathesis due to the absence of dense bodies in platelets.

Methods: In this report, we describe a case of a pair of Puerto Rican siblings with albinism that were clinically diagnosed with HPS during childhood. Since they did not harbor the founder changes in the HPS1 and HPS3 genes common in Puerto Ricans, as adults they wanted to know the type of albinism they had. We performed exome sequencing, validation by PCR, and cloning of PCR products followed by Sanger sequencing in the family members.

Results: We discovered no mutations that could explain an HPS diagnosis. Instead, we found the siblings were compound heterozygotes for 4 variants in the Tyrosinase gene: c.-301C>T, c.140G>A (rs61753180; p.G47D), c.575C>A (rs1042602; p.S192Y), and c.1205G>A (rs1126809; p.R402Q). Our results show that the correct diagnosis for the siblings is OCA1B.

Conclusion: Our study shows the importance of molecular testing when diagnosing a rare genetic disorder, especially in populations were the disease prevalence is higher.

Background: Patients with uncommon genetic conditions often face limited in-person resources for social and informational support. Hypermobile Ehlers-Danlos syndrome (hEDS) is a rare or underdiagnosed hereditary disorder of the connective tissue, and like those with similar diseases, patients with hEDS have begun to turn to social media in search of care and community. The aims of our study were to understand the usage habits and perceptions of utility of social media use for patients with hEDS in order to formulate suggestions for how clinicians may best engage these and similar patient populations about this topic.

Methods: We conducted both a quantitative survey and qualitative interviews with patients who had received a robust clinical diagnosis of hEDS.

Results: Twenty-four individuals completed the initial survey, and a subset of 21 of those participants completed an interview. Through thematic analysis, we identified four primary themes related to their experience with social media: (1) befriending others with their disease, (2) seeking and vetting information, (3) the risks and downsides of social media use, and (4) the desire for clinicians to discuss this topic with them.

Conclusion: We conclude by proposing five suggestions that emerge empirically from our data. These proposals will help clinicians engage their patients regarding social media use in order to promote its potential benefits and circumvent its potential harms as they pursue support for their hereditary condition.

Background: The protein kinase domain containing cytoplasmic (PKDCC) gene (OMIM#618821) is associated with bone development. Biallelic variants in the PKDCC gene can cause rhizomelic limb shortening with dysmorphic features.

Case report: A fetus was found to be rhizomelic limb shortening at 16 weeks of gestation and amniocentesis was performed at 19 weeks of gestation. Genomic DNA extracted from the amniotic fluid was subjected to chromosomal microarray analysis (CMA), and Trio-total whole-exome sequencing (Trio-WES). Sanger sequencing was used to verify the candidate pathogenic variants. CMA was normal, while Trio-WES identified two compound heterozygous variants in the PKDCC gene, namely c.417_c.423delCGGCGCG insTCATGGGCTCAGTACAC(p.G140fs*35) and c.345G>A (p.W115*,379). Then the fetus was aborted and the development of its bone cells were compared with that of a normal fetus of similar gestational age by histopathological examination. Clinical findings of the fetus were shortening humerus and femur, synophrys, much hair on the side face, simian line on the right palm, etc. Histopathological examination showed that the affected fetus had increased proliferative chondrocytes, widened proliferative bands, and delayed bone mineralization.

Conclusions: We reported a prenatal case of rhizomelic shortening of limbs caused by compound heterozygous variants in the PKDCC gene, which emphasized the important role of Trio-WES for diagnosis of skeletal dysplasia in fetuses.

Background: Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by variants in GLA gene leading to deficient α-galactosidase A enzyme activity. This deficiency leads to the accumulation of glycosphingolipids, particularly globotriaosylceramide (Gb3), in various tissues and organs, which can result in life-threatening complications. The clinical presentation of the disease can vary from the "classic" phenotype with pediatric onset and multi-organ involvement to the "later-onset" phenotype, which presents with predominantly cardiac symptoms. In recent years, advances in screening studies have led to the identification of an increasing number of variants of unknown significance that have not yet been described, and whose pathogenic role remains undetermined.

Methods: In this clinical report, we describe the case of an asymptomatic adult female who was found to have a new variant of unknown significance, p.Met70Val. Given the unknown pathogenic role of this variant, a thorough analysis of the potential organ involvement was conducted. The clinical data were analyzed retrospectively.

Results: The analysis revealed that there were no signs of significant organ involvement, and the benignity of the variant was confirmed.

Conclusion: This case underscores the importance of a comprehensive evaluation of new variants of unknown significance to establish their pathogenicity accurately.

Background: Dilated cardiomyopathy (DCM) is characterized by dilatation of the left ventricle, systolic dysfunction, and normal or reduced thickness of the left ventricular wall. It is a leading cause of heart failure and cardiac death at a young age. Cases with neonatal onset DCM were correlated with severe clinical presentation and poor prognosis. A monogenic molecular etiology accounts for nearly half of cases.

Family description: Here, we report a family with three deceased offspring at the age of 1 year old. The autopsy of the first deceased infant revealed a DCM. The second infant presented a DCM phenotype with a severely reduced Left Ventricular Ejection Fraction (LVEF) of 10%. Similarly, the third infant showed a severe DCM phenotype with LVEF of 30% as well, in addition to eccentric mitral insufficiency.

Results: Exome sequencing was performed for the trio (the second deceased infant and her parents). Data analysis following the autosomal dominant and recessive patterns of inheritance was carried out along with a mitochondrial pathways-based analysis. We identified a homozygous frameshift variant in the TNNI3 gene (c.204delG; p.(Arg69AlafsTer8)). This variant has been recently reported in the ClinVar database in association with cardiac phenotypes as pathogenic or likely pathogenic and classified as pathogenic according to ACMG.

Conclusion: Genetic counseling was provided for the family and a prenatal diagnosis of choronic villus was proposed in the absence of pre-implantation genetic diagnosis possibilities. Our study expands the case series of early-onset DCM patients with a protein-truncating variant in the TNNI3 gene by reporting three affected infant siblings.

Background: Serine residues in the protein backbone of heavily glycosylated proteoglycans are bound to glycosaminoglycans through a tetrasaccharide linker. UXS1 encodes UDP-glucuronate decarboxylase 1, which catalyzes synthesis of UDP-xylose, the donor of the first building block in the linker. Defects in other enzymes involved in formation of the tetrasaccharide linker cause so-called linkeropathies, characterized by short stature, radio-ulnar synostosis, decreased bone density, congenital contractures, dislocations, and more.

Methods: Whole exome sequencing was performed in a father and son who presented with a mild skeletal dysplasia, as well as the father's unaffected parents. Wild-type and mutant UXS1 were recombinantly expressed in Escherichia coli and purified. Enzyme activity was evaluated by LC-MS/MS. In vivo effects were studied using HeparinRed assay and metabolomics.

Results: The son had short long bones, normal epiphysis, and subtle metaphyseal changes especially in his legs. The likely pathogenic heterozygous variant NM_001253875.1(UXS1):c.557T>A p.(Ile186Asn) detected in the son was de novo in the father. Purified Ile186Asn-UXS1, in contrast to the wild-type, was not able to convert UDP-glucuronic acid to UDP-xylose. Plasma glycosaminoglycan levels were decreased in both son and father.

Conclusion: This is the first report linking UXS1 to short-limbed short stature in humans.

Background: Spastic paraplegia 11 (SPG11) is the most prevalent form of autosomal recessive hereditary spastic paraplegia, resulting from biallelic pathogenic variants in the SPG11 gene (MIM *610844).

Methods: The proband is a 36-year-old female referred for genetic evaluation due to cognitive dysfunction, gait impairment, and corpus callosum atrophy (brain MRI was normal at 25-years-old). Diagnostic approaches included CGH array, next-generation sequencing, and whole transcriptome sequencing.

Results: CGH array revealed a 180 kb deletion located upstream of SPG11. Sequencing of SPG11 uncovered two rare single nucleotide variants: the novel variant c.3143C>T in exon 17 (in cis with the deletion), and the previously reported pathogenic variant c.6409C>T in exon 34 (in trans). Whole transcriptome sequencing revealed that the variant c.3143C>T caused exon 17 skipping.

Conclusion: We report a novel sequence variant in the SPG11 gene resulting in exon 17 skipping, which, along with a nonsense variant, causes Spastic Paraplegia 11 in our proband. In addition, a deletion upstream of SPG11 was identified in the patient, whose implication in the phenotype remains uncertain. Nonetheless, the deletion apparently affects cis-regulatory elements of the gene, suggesting a potential new pathogenic mechanism underlying the disease in a subset of undiagnosed patients. Our findings further support the hypothesis that the origin of thin corpus callosum in patients with SPG11 is of progressive nature.

Background: Spinocerebellar ataxia 29 (SCA29) is a rare genetic disorder characterized by early-onset ataxia, gross motor delay, and infantile hypotonia, and is primarily associated with variants in the ITPR1 gene. Cases of SCA29 in Asia are rarely reported, limiting our understanding of this disease.

Methods: A female Korean infant, demonstrating clinical features of SCA29, underwent evaluation and rehabilitation at our outpatient clinic from the age of 3 months to the current age of 4 years. Trio-based genome sequencing tests were performed on the patient and her biological parents.

Results: The infant initially presented with macrocephaly, hypotonia, and nystagmus, with nonspecific findings on initial neuroimaging. Subsequent follow-up revealed gross motor delay, early onset ataxia, strabismus, and cognitive impairment. Further neuroimaging revealed atrophy of the cerebellum and vermis, and genetic analysis revealed a de novo pathogenic heterozygous c.800C>T, p.Thr267Met missense mutation in the ITPR1 gene (NM_001378452.1).

Conclusion: This is the first reported case of SCA29 in a Korean patient, expanding the genetic and phenotypic spectrum of ITPR1-related ataxias. Our case highlights the importance of recognizing early-onset ataxic symptoms, central hypotonia, and gross motor delays with poor ocular fixation, cognitive deficits, and isolated cerebellar atrophy as crucial clinical indicators of SCA29.