Molecular Genetics & Genomic Medicine最新文献

Background: Patients with 22q11.2 microduplication syndrome exhibit a high degree of phenotypic heterogeneity and incomplete penetrance, making prenatal diagnosis challenging due to phenotypic variability. This report aims to raise awareness among prenatal diagnostic practitioners regarding the variant's complexity, providing a basis for prenatal genetic counseling.

Methods: Family and clinical data of 31 fetuses with 22q11.2 microduplications confirmed by chromosomal microarray between June 2017 and June 2023 were considered.

Results: Primary prenatal ultrasound features of affected fetuses include variable cardiac and cardiovascular anomalies, increased nuchal translucency (≥3 mm), renal abnormalities, and polyhydramnios. More than half of fetuses considered showed no intrauterine manifestations; therefore, prenatal diagnostic indicators were primarily advanced maternal age or high-risk Down syndrome screening. Most fetuses had microduplications in proximal or central 22q11.2 regions, with only three cases with distal microduplications. Among parents of fetuses considered, 87% (27/31) continued the pregnancy. During follow-up, 19 cases remained clinically asymptomatic.

Conclusion: Nonspecific 22q11.2 microduplication features in fetuses and its mild postnatal disease presentation highlight the need to cautiously approach prenatal diagnosis and pregnancy decision-making. Increased clinical efforts should be made regarding providing parents with specialized genetic counseling, long-term follow-up, and fetal risk information.

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.

Background: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked recessive disorder that predisposes individuals to hemolysis due to an inborn error of metabolism. We performed a systematic literature review to evaluate G6PD deficiency as a possible etiology of nonimmune hydrops fetalis (NIHF) and severe fetal anemia.

Methods: PubMed, OVID Medline, Scopus, and clinicaltrials.gov were queried from inception until 31 April 2023 for all published cases of NIHF and severe fetal anemia caused by G6PD deficiency. Keywords included "fetal edema," "hydrops fetalis," "glucose 6 phosphate dehydrogenase deficiency," and "fetal anemia." Cases with workup presuming G6PD deficiency as an etiology for NIHF and severe fetal anemia were included. PRISMA guidelines were followed.

Results: Five cases of G6PD-related NIHF and one case of severe fetal anemia were identified. Four fetuses (4/6, 66.7%) were male and two fetuses (2/6, 33.3%) were female. Mean gestational age at diagnosis of NIHF/anemia and delivery was 32.2 ± 4.9 and 35.7 ± 2.4 weeks, respectively. Four cases (66.7%) required a cordocentesis for fetal transfusion, and two cases (33.3%) received blood transfusions immediately following delivery. Among the four multigravida cases, two (50%) noted previous pregnancies complicated by neonatal anemia. When reported, the maternal cases included two G6PD deficiency carrier patients and two G6PD-deficient patients. Exposures to substances known to cause G6PD deficiency-related hemolysis occurred in 3/6 (50%) cases.

Conclusion: Six cases of NIHF/severe fetal anemia were associated with G6PD deficiency. While G6PD deficiency is an X-linked recessive condition, female fetuses can be affected. Fetal G6PD deficiency testing can be considered if parental history indicates, particularly if the standard workup for NIHF is negative.

Background: Marfan syndrome (MFS) is a hereditary connective tissue disorder involving multiple systems, including ophthalmologic abnormalities. Most cases are due to heterozygous mutations in the fibrillin-1 gene (FBN1). Other associated genes include LTBP2, MYH11, MYLK, and SLC2A10. There is significant clinical overlap between MFS and other Marfan-like disorders.

Purpose: To expand the mutation spectrum of FBN1 gene and validate the pathogenicity of Marfan-related genes in patients with MFS and ocular manifestations.

Methods: We recruited 318 participants (195 cases, 123 controls), including 59 sporadic cases and 88 families. All patients had comprehensive ophthalmic examinations showing ocular features of MFS and met Ghent criteria. Additionally, 754 cases with other eye diseases were recruited. Panel-based next-generation sequencing (NGS) screened mutations in 792 genes related to inherited eye diseases.

Results: We detected 181 mutations with an 84.7% detection rate in sporadic cases and 87.5% in familial cases. The overall detection rate was 86.4%, with FBN1 accounting for 74.8%. In cases without FBN1 mutations, 23 mutations from seven Marfan-related genes were identified, including four pathogenic or likely pathogenic mutations in LTBP2. The 181 mutations included 165 missenses, 10 splicings, three frameshifts, and three nonsenses. FBN1 accounted for 53.0% of mutations. The most prevalent pathogenic mutation was FBN1 c.4096G>A. Additionally, 94 novel mutations were detected, with 13 de novo mutations in 14 families.

Conclusion: We expanded the mutation spectrum of the FBN1 gene and provided evidence for the pathogenicity of other Marfan-related genes. Variants in LTBP2 may contribute to the ocular manifestations in MFS, underscoring its role in phenotypic diversity.

Background: This study aimed to identify disease-causing variants within a Chinese family affected by Birt-Hogg-Dubé syndrome (BHDS), which arises from an autosomal dominant inheritance pattern attributed to variants in the folliculin (FLCN) gene, recognized as a tumor suppressor gene.

Methods: A Chinese proband diagnosed with BHDS due to renal tumors underwent next-generation sequencing (NGS), revealing a novel variant in the FLCN gene. Sanger sequencing was subsequently performed on blood samples obtained from family members to confirm the presence of this variant.

Results: A novel germline frameshift variant (NM_144997.5:c.977dup) was identified in five individuals among the screened family members, marking the first report of this variant. Additionally, a somatic frameshift variant (NM_144997.5:c.1252del) was detected in the renal tumors of the proband. No variant was detected in unaffected family members.

Conclusions: A novel heterozygous variant was identified in exon 9 of the FLCN gene, which broadens the spectrum of FLCN variants. We recommend that molecular analysis of the FLCN gene be performed in patients with suspected BHDS and their families.

Background: Glutaric aciduria type II (GA2) is a rare genetic disorder inherited in an autosomal recessive manner. Double dosage mutations in GA2 corresponding genes, ETFDH, ETFA, and ETFB, lead to defects in the catabolism of fatty acids, and amino acids lead to broad-spectrum phenotypes, including muscle weakness, developmental delay, and seizures. product of these three genes have crucial role in transferring electrons to the electron transport chain (ETC), but are not directly involve in ETC complexes.

Methods: Here, by using exome sequencing, the cause of periodic cryptic gastrointestinal complications in a 19-year-old girl was resolved after years of diagnostic odyssey. Protein modeling for the novel variant served as another line of validation for it.

Results: Exome Sequencing (ES) identified two variants in ETFDH: ETFDH:c.926T>G and ETFDH:c.1141G>C. These variants are likely contributing to the crisis in this case. To the best of our knowledge at the time of writing this manuscript, variant ETFDH:c.926T>G is reported here for the first time. Clinical manifestations of the case and pathological analysis are in consistent with molecular findings. Protein modeling provided another line of evidence proving the pathogenicity of the novel variant. ETFDH:c.926T>G is reported here for the first time in relation to the causation GA2.

Conclusion: Given the milder symptoms in this case, a review of GA2 cases caused by compound heterozygous mutations was conducted, highlighting the range of symptoms observed in these patients, from mild fatigue to more severe outcomes. The results underscore the importance of comprehensive genetic analysis in elucidating the spectrum of clinical presentations in GA2 and guiding personalized treatment strategies.

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: 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.