Molecular Genetics & Genomic Medicine最新文献

Background: The highest mortality and morbidity worldwide is associated with atherosclerotic cardiovascular disease (ASCVD), which has in background both environmental and genetic risk factors. Apolipoprotein L1 (APOL1) variability influences the risk of ASCVD in Africans, but little is known about the APOL1 and ASCVD in other ethnic groups.

Methods: To investigate the role of APOL1 and ASCVD, we have genotyped four (rs13056427, rs136147, rs10854688 and rs9610473) APOL1 polymorphisms in a group of 1541 male patients with acute coronary syndrome (ACS) and 1338 male controls.

Results: Individual APOL1 polymorphisms were not associated with traditional CVD risk factors such as smoking, hypertension or diabetes prevalence, with BMI values or plasma lipid levels. Neither individual polymorphisms nor haplotypes were associated with an increased risk of ACS nor did they predict total or cardiovascular mortality over the 10.2 ± 3.9 years of follow-up.

Conclusions: We conclude that APOL1 genetic variability has no major effect on risk of ACS in Caucasians.

Background: Feeding difficulties frequently co-occur with multisystem disorders attributed to rare genetic diseases. In this study, we aimed to describe the genetic manifestations and phenotype spectrum in infants experiencing feeding difficulties.

Methods: This case series included infants under 6 months old with feeding difficulties admitted to the neonatal department of Children's Hospital, Zhejiang University School of Medicine from October 2018 to May 2022. All infants underwent whole-exome sequencing (WES) during hospitalisation, and their clinical phenotypes and genetic results were analyzed.

Results: Among 28 infants studied, nine were preterm and 19 were full-term. Median admission age was 13.5 days (IQR 6.5, 35), with a median hospital stay of 16 days (IQR 10.5, 30). Overall, 12 (42.9%) cases were complicated with multiple malformations. Abnormal muscle tone (53.6%) and neurological issues (42.9%) were notable prevalent in these infants. Cranial MR abnormalities were noted in 96.2% of cases. Based on the combined analysis of WES results and clinical phenotypes, a total of 22 (78.3%) patients displayed disease-related genetic variation identified through WES; among them, 15 (53.6%) patients received genetic diagnoses, while 7 (25%) patients were suspected diagnoses. Positive findings were more frequent in full-term (89.5%) than preterm infants (55.6%). Ultimately, 24 (85.7%) patients were discharged alive, with 75% requiring post-discharge tube feeding. Following discharge, five patients developed new symptoms linked to genetic variants, and two patients died.

Conclusions: Feeding difficulty may constitute a facet of the phenotypic spectrum of rare genetic diseases. Whole-exome sequencing can enhance molecular diagnosis accuracy for infants with feeding difficulties.

Background: Biallelic variants in the major facilitator superfamily domain containing 8 gene (MFSD8) are associated with distinct clinical presentations that range from typical late-infantile neuronal ceroid lipofuscinosis type 7 (CLN7 disease) to isolated adult-onset retinal dystrophy. Classic late-infantile CLN7 disease is a severe, rare neurological disorder with an age of onset typically between 2 and 6 years, presenting with seizures and/or cognitive regression. Its clinical course is progressive, leading to premature death, and often includes visual loss due to severe retinal dystrophy. In rare cases, pathogenic variants in MFSD8 can be associated with isolated non-syndromic macular dystrophy with variable age at onset, in which the disease process predominantly or exclusively affects the cones of the macula and where there are no neurological or neuropsychiatric manifestations.

Methods: Here we present longitudinal studies on four adult-onset patients who were biallelic for four MFSD8 variants.

Results: Two unrelated patients who presented with adult-onset ataxia and had macular dystrophy on examination were homozygous for a novel variant in MFSD8 NM_152778.4: c.935T>C p.(Ile312Thr). Two other patients presented in adulthood with visual symptoms, and one of these developed mild to moderate cerebellar ataxia years after the onset of visual symptoms.

Conclusions: Our observations expand the knowledge on biallelic pathogenic MFSD8 variants and confirm that these are associated with a spectrum of more heterogeneous clinical phenotypes. In MFSD8-related disease, adult-onset recessive ataxia can be the presenting manifestation or may occur in combination with retinal dystrophy.

Background: Inherited glycosylphosphatidylinositol (GPI) deficiency is an autosomal recessive disease and a set of syndromes caused by different genes involved in the biosynthesis of phosphatidylinositol characterized by severe cognitive disability, elevated serum alkaline phosphatase (ALP) levels, and distinct facial features. This report presents a patient with inherited GPI deficiency caused by a homozygous frameshift variant of PGAP3 due to uniparental isodisomy (UPiD) on chromosome 17.

Method: Clinical characteristics of the patient were collected. Microarray analysis followed by adaptive sampling sequencing targeting chromosome 17 was used for the identification of variants. Sanger sequencing was used to confirm the variant in the target region.

Results: The patient was born at 38 weeks of gestation with a birthweight of 3893 g. He had a distinctive facial appearance with hypertelorism, wide nasal bridge, and cleft soft palate. Postnatal head magnetic resonance imaging revealed a Blake's pouch cyst. The serum ALP level was 940 IU/L at birth and increased to 1781 IU/L at 28 days of age. Microarray analysis revealed region of homozygosity in nearly the entire region of chromosome 17, leading to the diagnosis of UPiD. Adaptive sampling sequencing targeting chromosome 17 confirmed the homozygous variant NM_033419:c.778dupG (p.Val260Glyfs*14) in the PGAP3 gene, resulting in a diagnosis of inherited GPI deficiency.

Conclusion: This is the first report of inherited GPI deficiency caused by UPiD. Inherited GPI deficiency must be considered in patients with unexplained hyperphosphatasemia.

Background: X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder attributed to ABCD1 mutations. Case reports with predominant brainstem involvement are rare.

Case presentation: In this study, we reported a plateau male worker of X-ALD characterized by progressive weakness accompanied by gait instability, mild nystagmus, and constipation. After 2 years of onset, a brain Magnetic Resonance Image (MRI) scan showed no abnormality but genetic analysis revealed a heterozygous mutation (c.1534G>A) in the ABCD1 gene. After 7 years of onset, although the patient was given aggressive dietary and symptomatic treatment in the course of the disease, a brain MRI scan showed predominantly brainstem damage, but serum concentrations of very long-chain fatty acids were normal, and he had been bedridden for almost 2 years with severe bladder dysfunction, forcing him to undergo cystostomy. The patient was discharged with improved urinary retention and renal function.

Conclusions: We reported an X-ALD patient with a novel ABCD1 variation characterized by brainstem damage and retrospectively summarized the clinical manifestation, MRI features, and genetic features of X-ALD patients with brainstem damage.

Background: Hereditary diffuse gastric cancer (HDGC) (OMIM# 137215) is an autosomal dominant cancer syndrome associated with CDH1 (OMIM# 192090) mutations. Prophylactic total gastrectomy (PTG) is the most recommended preventive treatment when a pathogenic mutation is found. However, the increasing use of genetic testing has led to the identification of incidental CDH1 mutations in individuals without a family history of gastric cancer. It remains unclear whether these patients should undergo prophylactic total gastrectomy.

Methods: Germline DNA, obtained from peripheral blood, was analysed by NGS.

Results: A 47-year-old woman was diagnosed with high-grade serous ovarian carcinoma, FIGO stage IIIC, with a Homologous Recombination Deficiency (HRD) GIS status of 78 (positive, cut-off: 43). She received chemotherapy and niraparib treatment. A multigene panel test revealed no pathogenic mutations in BRCA1 (OMIM# 113705)/BRCA2 (OMIM# 600185) genes, but a de novo deletion of exon 16 in CDH1 was found incidentally. She had no previous family history of gastric or breast cancer. The patient was enrolled in a surveillance program involving periodic endoscopy and was diagnosed with diffuse gastric cancer through biopsies of a pale area in the antrum after 1 year of close endoscopic follow-up.

Conclusion: This case presents supportive evidence for the pathogenic classification of the loss of the last exon of CDH1.

Background: Pompe Disease (PD) is a metabolic myopathy caused by variants in the GAA gene, resulting in deficient enzymatic activity. We aimed to characterize the clinical features and related genetic variants in a series of Mexican patients.

Methods: We performed a retrospective study of clinical records of patients diagnosed with LOPD, IOPD or pseudodeficiency.

Results: Twenty-nine patients were included in the study, comprising these three forms. Overall, age of symptom onset was 0.1 to 43 years old. The most frequent variant identified was c.-32-13T>G, which was detected in 14 alleles. Among the 23 different variants identified in the GAA gene, 14 were classified as pathogenic, 5 were likely pathogenic, and 1 was a variant of uncertain significance. Two variants were inherited in cis arrangement and 2 were pseudodeficiency-related benign alleles. We identified two novel variants (c.1615 G>A and c.1076-20_1076-4delAAGTCGGCGTTGGCCTG).

Conclusion: To the best of our knowledge, this series represent the largest phenotypic and genotypic characterization of patients with PD in Mexico. Patients within our series exhibited a combination of LOPD and IOPD associated variants, which may be related to genetic diversity within Mexican population. Further population-wide studies are required to better characterize the incidence of this disease in Mexican population.

Background: Synonymous variants are non-pathogenic due to non-substitution of amino acids. However, synonymous exonic terminal nucleotide substitutions may affect splicing. Splicing variants are easily analyzed at RNA level for genes expressed in blood cells. Minigene analysis provides another method for splicing variant analysis of genes that are poorly or not expressed in peripheral blood.

Methods: Whole exome sequencing was performed to screen for potential pathogenic mutations in the proband, which were validated within the family by Sanger sequencing. The pathogenicity of the synonymous mutation was analyzed using the minigene technology.

Results: The proband harbored the compound heterogeneous variants c. [291G >A; 572-50C >T] and c.681 + 1G >T in F7, of which the synonymous variant c.291G >A was located at the terminal position of exon 3. Minigene analysis revealed exon3 skipping due to this mutation, which may have subsequently affected protein sequence, structure, and function.

Conclusion: Our finding confirmed the pathogenicity of c.291G >A, thus extending the pathogenic mutation spectrum of F7, and providing insights for effective reproductive counseling.

Background: Autosomal recessive spastic ataxia ofCharlevoix-Saguenay (ARSACS) is a rare neurodegenerative disorder characterizedby early-onset cerebellar ataxia, peripheral sensorimotor neuropathy, and lowerlimb spasticity. We present clinical andgenetic data of the first Bulgarian patients diagnosed with ARSACS by wholeexome sequencing (WES).

Methods: Variant filtering was performed usinglocally established pipeline and the selected variants were analysed by Sangersequencing. All patients underwent clinical examination and testingincluding the standard rating scales for spastic paraplegia and ataxia.

Results: Five different SACS gene variants, three of which novel, have been identified inpatients from three different ethnic groups. In addition to the classicalclinical triad, brain MRI revealed cerebellar atrophy, linear pontineT2-hypointensities, and hyperintense rim lateral tothalamus combined with retinal nerve fiber layer thickening on opticcoherence tomography (OCT).

Conclusion: We expand the mutation, geographic, and phenotypic spectrum of ARSACS, adding Bulgaria to the world map of the disease, and drawing attention to the fact that it is still misdiagnosed. We demonstrated that brain MRI and OCT are necessary clinical tests for ARSACS diagnosis, even if one of the cardinal clinical features is lacking.

Background: We clinically and genetically evaluated a Taiwanese boy presenting with developmental delay, organomegaly, hypogammaglobulinemia and hypopigmentation without osteopetrosis. Whole-exome sequencing revealed a de novo gain-of-function variant, p.Tyr715Cys, in the C-terminal domain of ClC-7 encoded by CLCN7.

Methods: Nicoli et al. (2019) assessed the functional impact of p.Tyr715Cys by heterologous expression in Xenopus oocytes and evaluating resulting currents.

Results: The variant led to increased outward currents, indicating it underlies the patient's phenotype of lysosomal hyperacidity, storage defects and vacuolization. This demonstrates the crucial physiological role of ClC-7 antiporter activity in maintaining appropriate lysosomal pH.

Conclusion: Elucidating mechanisms by which CLCN7 variants lead to lysosomal dysfunction will advance understanding of genotype-phenotype correlations. Identifying modifier genes and compensatory pathways may reveal therapeutic targets. Ongoing functional characterization of variants along with longitudinal clinical evaluations will continue advancing knowledge of ClC-7's critical roles and disease mechanisms resulting from its dysfunction. Expanded cohort studies are warranted to delineate the full spectrum of associated phenotypes.