Molecular Genetics & Genomic Medicine最新文献

Background: The 22q11.2 deletion syndrome (22q11.2DS) is mostly caused by deletions of 3 and 1.5 Mb, referred to as typical deletions, although atypical deletions have also been reported. The commonest features are congenital heart disease, immunodeficiency, facial dysmorphism, and developmental delay. However, phenotypic variability is remarkable, and the underlying mechanisms remain poorly understood.

Objective: To determine copy number variations (CNVs) in the 22q11.2 region and their association with clinical manifestations in Mexican patients with suspected 22q11.2DS.

Methods: Fluorescence in situ Hybridization (FISH) and Multiplex Ligation-dependent Probe Amplification (MLPA) assays were performed in 80 patients with suspected 22q11.2DS. Clinical characterization was carried out according to the criteria used by the 22q11.2 Consortium.

Results: FISH detected deletions in 51%, while MLPA detected CNVs in 54%. Typical deletions were observed in 86% of patients, whereas atypical deletions were found in 14%, including CNVs involving single genes (TBX1, TOP3B, and PRODH). Three families were identified with the 3 Mb deletion and exhibited a heterogeneous phenotype that cannot be explained by the microdeletion alone.

Conclusion: 22q11.2DS is a complex disorder for which MLPA is recommended to detect atypical deletions in FISH-negative patients, and to define deletion size, breakpoints, and genes in FISH-positive ones.

Background: We identified a novel ABCD1 variant (c.773T>G, p.Leu258Arg, NM_000033.4) in a Chinese pedigree affected by X-linked adrenoleukodystrophy (X-ALD). This missense variant in exon 1 is predicted to be pathogenic and likely constitutes the genetic basis of the disease phenotype in this family.

Methods: ABCD1 gene sequencing was performed in the Chinese pedigree. The pathogenicity of identified variants was assessed using computational prediction tools. Subcellular localization studies were conducted, and very-long-chain fatty acid (VLCFA) levels were quantified in patient-derived samples.

Results: Sequencing analysis identified a hemizygous missense variant in the ABCD1 gene (c.773T>G; p.Leu258Arg). In silico pathogenicity prediction using SIFT and PolyPhen-2 algorithms classified the p.Leu258Arg substitution as deleterious. Functional characterization revealed that the p.Leu258Arg variant impairs the peroxisomal membrane localization of the ABCD1 protein. Consistent with the established role of ABCD1 in peroxisomal β-oxidation, individuals harboring this variant exhibited significantly elevated serum levels of VLCFA. Specifically, the C26:0/C22:0 ratio was elevated 2.8-fold compared to control values, confirming impaired VLCFA metabolism.

Conclusion: In accordance with the "Standards and Guidelines for the Interpretation of Sequence Variants" established by the American College of Medical Genetics and Genomics (ACMG), we assessed the pathogenicity of the novel ABCD1 gene variant c.773T>G. This variant meets the following ACMG evidence criteria: PM1 (located within a critical functional domain or mutational hotspot known to lack benign variation); PM2 (absent or observed at very low frequency in population databases e.g., gnomAD, EXAC, 1000 Genomes); PP3 (multiple in silico prediction tools consistently suggest a deleterious effect on the gene or gene product). Integrating this evidence (PM1 + PM2 + PP3), the variant is classified as likely pathogenic based on ACMG guidelines. Experimental data from this study further substantiate the pathogenicity of the c.773T>G variant located in exon 1 of the ABCD1 gene. This finding broadens the spectrum of known pathogenic mutations in ABCD1 associated with X-ALD and provides crucial information for the molecular diagnosis of affected patients.

Background: Pallister-Hall syndrome (PHS) is an extremely rare genetic disorder. It presents as a polymalformative syndrome affecting craniofacial structures, the central nervous system, limbs, various internal organs, and the endocrine system. It is considered a ciliopathy, as it is associated with loss-of-function variants in the GLI3 gene, a transcription factor essential for primary cilium signaling. The syndrome shows marked clinical heterogeneity depending on the type of genetic variant, which makes diagnosis challenging. It is usually suspected at an early age when a hypothalamic hamartoma is associated with polydactyly. Endocrine manifestations are often linked to the hamartoma, further complicating diagnosis.

Case presentation: A 23-year-old Colombian patient presented with a history of hypothalamic hamartoma, gelastic seizures, postaxial polydactyly of hands and feet, and craniofacial dysmorphisms. Physical examination revealed dolichocephaly, bilateral epicanthus, broad nasal bridge, short and broad neck, mild cervical kyphosis, mild scoliosis, micrognathia, bilateral ulnar deviation of the fourth and fifth fingers, and overlapping toes on both feet. No genital anomalies were found. Neuropsychological evaluation reported a borderline intellectual quotient of 78. Whole-exome sequencing identified a de novo heterozygous pathogenic variant in GLI3 (c.2151del; p.(Gln71HisfsTer16)), confirmed by Sanger sequencing.

Conclusions: We report the first case described in Colombia of a previously unreported truncating genetic variant. We performed a clinical-molecular correlation in a 23-year-old adult whose diagnosis of PHS was delayed until adulthood, years after the initial identification of a hypothalamic hamartoma, refractory gelastic seizures, polydactyly, and mild cognitive impairment. This case broadens the clinical spectrum regarding the viability of patients with PHS into adulthood, showing that it is not restricted to the severe neonatal or infantile presentations classically described.

Background: Tetrasomy 9p is a rare chromosomal disorder with distinct clinical features, but wide phenotypic variability. Historically, tetrasomy 9p has been detected by conventional cytogenetic analysis, but newer technologies such as non-invasive prenatal testing (NIPT) and chromosome microarray (CMA) allow the identification of cases that would previously have gone undetected. Here we describe a girl with a mosaic isodicentric chromosome 9 (idic(9)), ascertained through NIPT, but with diagnosis not confirmed until after birth.

Methods: Chromosomal microarray (CMA) was performed on DNA extracted from saliva, buccal and blood samples from a clinically well newborn to confirm abnormal prenatal findings. Subsequent conventional G-banded analysis was performed on stimulated T-lymphocyte culture following diagnosis of mild speech delay and hearing loss.

Results: Copy number gain at 9p24.3q22.32 was identified on CMA in three independent samples. G-banded analysis subsequently identified a supernumerary isodicentric chromosome 9 in one out of 105 cells examined, with breakpoints at 9p24 and 9q22.3, representing a partial tetrasomy of chromosome 9.

Conclusion: Tetrasomy 9p has wide phenotypic variability due to mosaicism. This unusually mild case of tetrasomy 9p would have almost certainly gone undetected prior to the implementation of NIPT and CMA. This report highlights the value of reporting cases ascertained through high-resolution technologies to facilitate early diagnosis and prognosis and enable a better understanding of this condition through precise breakpoint mapping.

Objective: To report the clinical manifestations, treatment, and genetic diagnosis of a patient with osteo-oto-hepato-enteric (O2HE) syndrome.

Case presentation: A retrospective analysis was performed on a Chinese premature infant born at 36 + 5 weeks of gestation. The analysis included maternal pregnancy and delivery history, prenatal ultrasound findings, clinical manifestations, diagnosis and treatment process, and UNC45A gene mutation results for the infant and parents. A literature review was also conducted. The mother had a history of six spontaneous abortions. A late-pregnancy prenatal ultrasound revealed polyhydramnios and diffuse intestinal dilation. The infant developed watery stools and diarrhea shortly after birth and was clinically suspected to have congenital chloride diarrhea. Supportive treatment was administered, and whole-exome sequencing was performed for the family. Two heterozygous mutations were identified in the UNC45A gene, including c.2455C > T (p.Arg819Ter), a novel, previously unreported variant. The infant was ultimately diagnosed with osteo-oto-hepatoenteric syndrome.

Conclusion: Genetic analysis of the UNC45A gene is valuable for diagnosing O2HE syndrome. The novel mutation c.2455C > T (p.Arg819Ter) enriches the mutation spectrum of UNC45A, providing further theoretical support for diagnosis and genetic counseling of O2HE.

Background: Human chimerism is rare, and most prevalent with discordant chromosomal sex. We report a male 46,XY/46,XY chimera, born through a spontaneously conceived pregnancy to a healthy 32-year-old G1P0 Indian, African, and Scottish female and her 34-year-old healthy Chinese partner. The prenatal presentation and postnatal outcomes are described.

Methods: A prenatal cell-free DNA screening test, amniocentesis with QF-PCR and SNP microarray, and postnatal microarray and FISH study on peripheral blood, placenta, and umbilical cord were used to evaluate chimerism.

Results: The prenatal cell-free screening test revealed high risk for triploidy/vanishing twin, but there was no confirmation from early ultrasound. Subsequent QF-PCR on amniocytes showed a profile suggestive of a tetragametic chimera. G-banding showed a 46,XY karyotype. A SNP microarray detected two copy number gains of uncertain significance on chromosome 6q, derived from the father who was a balanced carrier of ins(6;11). A postnatal microarray and FISH study confirmed the presence of two cell lines, each with a 46,XY complement but with different submicroscopic structural changes including recombinant and insertion changes. Clinical evaluations of the child at birth and 8 weeks of age were coordinated to detect the presence of chimeric symptoms.

Conclusion: With a confirmed incidental finding of 46,XY/46,XY chimerism, we present that underlying same-sex chimerism may be under-recognized.

Introduction: Spinal muscular atrophy (SMA), caused by pathogenic variants in the survival motor neuron (SMN) gene, is the most common genetic cause of mortality in children under the age of two. Prior reports of obstetric sonograms performed in pregnancies with severe forms of fetal SMA have discrepant findings that may stem from a failure to account for the SMN2 copy number.

Methods: We present a neonate diagnosed with SMA type 0 postnatally (0SMN1/1SMN2 genotype). Antenatally, the fetus was noted to have HLHS (hypoplastic left heart syndrome), 2:1 AV block (atrioventricular), thickened nuchal translucency, polyhydramnios, and perceived maternal decreased fetal movement, and the mother declined genetic testing. A literature search was conducted to analyze potential prenatal findings in severe SMA type 0.

Results: The most common associations from 32 cases of SMA type 0 include cardiac defects, increased NT (nuchal translucency), decreased fetal movement, and contractures noted postnatally. Other associations that were present in the literature and in our case include nonvertex presentation, polyhydramnios, and fractures after birth.

Conclusion: Prenatal onset SMA type 0 with one copy of SMN2 appears to have a distinct phenotype. Cardiac anomalies, increased nuchal translucency, and decreased maternal perception of fetal movement in the third trimester are the most frequent findings, and if found, should prompt SMA testing.

Background: In the diagnostic process of monogenic genetic disorders, identifying pathogenic variants is a crucial step. Thanks to the widespread adoption of Next-Generation Sequencing (NGS) technology, diagnostic efficiency has been significantly enhanced. However, with the increasing demand for diagnostic accuracy in clinical practice for monogenic genetic diseases, accurately and swiftly pinpointing pathogenic variants among numerous candidate variants remains a significant challenge. The complexity of data analysis and interpretation continues to limit both the efficiency and accuracy of diagnosis.

Methods: In this study, we have developed an innovative phenotype-driven algorithm, geneEX. This algorithm integrates large language model technology to accurately extract phenotypes from clinical information and automatically acquire Human Phenotype Ontology (HPO) information through a semantic vector representation model, thereby identifying HPO-associated genes. Additionally, it supports semantic matching between patients' free-text phenotypic descriptions and disease phenotypes, further enhancing the identification of pathogenic genes. The algorithm can rank candidate causative variants, enabling rapid and precise identification of potential pathogenic variants in rare genetic disorders.

Results: geneEX demonstrates commendable performance in ranking pathogenic variants across both virtual and clinical datasets. The supplementary matching of phenotypes in free-text form significantly enhances the precision of candidate variant prioritization for samples.

Conclusion: geneEX has achieved automated HPO acquisition through its independently developed phenotype extraction and standardization methods, thereby enabling the full-process automated identification from clinical samples to pathogenic variants. Additionally, by integrating free-text phenotypic descriptions with disease phenotype matching, it enhances the accuracy of pathogenic gene identification. This innovative approach significantly improves the precision and efficiency of identifying pathogenic variants in rare genetic disorders, providing robust support for the diagnosis of monogenic diseases.

Background: Classical homocystinuria (HCU), caused by cystathionine beta-synthase (CBS) deficiency, exhibits significant geographic variability in its mutational spectrum. Although over 191 CBS mutations have been reported worldwide, Chinese cases remain rare and lack common hotspot mutations. This study aimed to characterize novel CBS variants in a Chinese family to expand the known mutational spectrum and inform genetic counseling practices.

Materials and methods: A Chinese Yi family affected by HCU was analyzed. Clinical features, whole-exome sequencing (WES), and metabolic data were collected. Ancestry composition was evaluated using principal component analysis (PCA) and ADMIXTURE analysis. The pathogenicity of CBS variants was assessed through three-dimensional protein modeling, Western blotting, and enzyme activity assays.

Results: The proband, a 9-year-old girl with lens dislocation and seizures, carried compound heterozygous CBS mutations: c.1006C>T (p.Arg336Cys) and c.1061_1069del (p.Val354_Val356del), both located within the catalytic domain of the CBS protein. Structural and functional analyses demonstrated that the latter variant disrupts CBS expression and enzymatic activity. Her asymptomatic brother also carried the same compound heterozygous variants and exhibited mild hyperhomocysteinemia. Ancestry analysis revealed predominant East Asian ancestry with 5.2% Central African Pygmy admixture.

Conclusion: This study identifies the first CBS c.1061_1069del variant and confirms c.1006C>T pathogenicity in China. The findings expand the CBS mutation spectrum, underscore the importance of ethnicity-specific variants, and provide valuable insights for prenatal diagnosis and genetic counseling in Chinese populations.