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PubMed1993

Differential expression of transporters for norepinephrine and glutamate in wild type, variant, and WNT1-expressing PC12 cells.

Wild type PC12 pheochromocytoma cells express a Na(+)-dependent norepinephrine transporter that operates in the uptake of catecholamines, including dopamine. This transporter is not expressed in two spontaneously occurring flat cell variants of PC12 or in two other flat cell variants whose phenotype was induced by expression of the Wnt-1 oncogene. However, each of the flat cell variants, including those that express Wnt-1, exhibit a Na(+)-dependent, Cl(-)-independent glutamate/aspartate transporter activity that is not present in wild type PC12 cells. The flat cell variants took up glycine by a Na(+)-dependent process as well as did wild type cells. All of the flat cell variants have decreased levels of norepinephrine transporter mRNA but normal levels of glycine transporter mRNA. Glutamate/aspartate transporter mRNA was detected only in the variants that exhibited glutamate/aspartate transporter activity, and the nucleotide sequence of a partial glutamate/aspartate transporter cDNA from these cells demonstrated that it was the glial form of the transporter that was expressed. These variants were more sensitive than was wild type PC12 to alanosine, a toxic aspartate analog that enters cells by a transporter-mediated system such as the glutamate/aspartate transporter; however, these variants were as sensitive as wild type cells to another toxic aspartate analog, N-(phosphonacetyl)-L-aspartic acid, which is believed to enter cells by endocytosis. We suggest that the Wnt-1 gene product, or a homolog, may be involved in glial differentiation and that the mechanisms that alter the expression of the norepinephrine and glutamate/aspartate transporters in wild type and variant PC12 cells may also operate to regulate neurotransmitter transporter expression in vivo.

Alanine↗

PubMed1993

A variant of t-PA (T103N, KHRR 296-299 AAAA) that, by bolus, has increased potency and decreased systemic activation of plasminogen.

In the accompanying paper, we reported that the properties of decreased plasma clearance rate, increased fibrin specificity, and resistance to inactivation by PAI-1 could be effectively combined in the t-PA variant T103N, KHRR 296-299 AAAA. In the current study we evaluated the in vivo efficacy of this variant as well as variants containing the individual mutations T103N and KHRR 296-299 AAAA. Plasma clearance and in vivo lysis of whole blood and platelet-rich clots were determined in a rabbit arterio-venous shunt model. The T103N containing variants were administered as an intravenous (i.v.) bolus. KHRR 296-299 AAAA and t-PA were infused i.v. over 90 min. The clearance rate of the KHRR 296-299 AAAA variant was similar to t-PA. However, the clearance of the T103N and T103N, KHRR 296-299 AAAA variants were 8 and 6-fold reduced, respectively. Potency of the variants relative to t-PA on whole blood clots ranged from 0.9 (T103N, KHRR 296-299 AAAA) to 1.7 (T103N). Relative potency on platelet-rich clots ranged from 2.4 (T103N) to 4.2 (T103N, KHRR 296-299 AAAA). Fibrinogen concentrations in rabbits 120 min after dosing with a 2.5 mg/kg bolus were: 24, 16, 82, and 77% of initial for t-PA; T103N; KHRR 296-299 AAAA; and T103N, KHRR 296-299 AAAA treatment groups, respectively. These results suggest that the T103N, KHRR 296-299 AAAA variant of t-PA, given as a bolus, could result in greater efficacy, particularly on refractory platelet-rich clots, without inducing the severe systemic lytic state produced by a bolus of a less fibrin specific variant.

Animals↗

PubMed1993

Expression of a constitutively active estrogen receptor variant in the estrogen receptor-negative BT-20 human breast cancer cell line.

Estrogen receptor (ER) expression by breast tumors is an important predictor of disease-free survival in breast cancer patients and, more importantly, is a strong predictor of response to endocrine therapy. Variant forms of the ER may play an important role in the loss of hormone responsiveness and the progression to hormone independence. We have examined a panel of human breast tumor cell lines, both ER-positive and ER-negative, and have identified an ER mRNA variant containing a deletion of exon 5 in the ER-negative BT-20 and ER-positive MCF-7 cell lines. This exon 5 deletion variant has been previously reported to be overexpressed in ER-negative/progesterone receptor-positive breast tumors. Using RNase protection analysis, we have found that the predominant ER transcript in the BT-20 cells is the exon 5 deletion variant, while the principal transcript in MCF-7 cells is the wild-type ER mRNA. The variant ER transcript is translated into a truncated receptor protein of approximately M(r) 42,000 when expressed in yeast and, more important, in breast tumor cells. This is the first demonstration of an exon 5 deletion variant ER protein. Functional analysis has shown that this variant ER possesses constitutive transcriptional regulatory activity with respect to an estrogen-regulated reporter gene construct in a yeast expression system. The presence of this ER variant in breast tumor cell lines, as well as breast tumor biopsies and uterine tissue, suggests that it is a naturally occurring variant that may arise by alternative splicing, and whose overexpression may be involved in the progression of breast tumors to a hormone-independent state.

Base Sequence↗

PubMed1996

Effects of an exon 5 variant of the estrogen receptor in MCF-7 breast cancer cells.

The estrogen receptor gene gives rise to variant mRNAs, generated by alternative mRNA splicing, as well as the full-length mRNA containing eight coding exons. It has been postulated that one of these, the exon 5 variant, may be important in the development of hormone-independent and anti-estrogen-resistant breast cancer since it has the potential to encode a truncated receptor that retains the N-terminal activation domain AF-1, but lacks the hormone-binding domain. We have expressed the variant using an inducible promoter in estrogen receptor-positive MCF-7 cells and analyzed the effect of the variant protein on gene expression and cell growth. Inducible expression was validated using a specific antiserum that recognized a novel epitope on the exon 5 variant. The variant was able to stimulate transcription of a reporter gene in transiently transfected chicken embryo fibroblasts in the absence of hormone but showed weak constitutive activity when it was stably expressed in MCF-7 cells. The variant had no effect on the expression of the estrogen target genes, pS2, and the progesterone receptor. Finally, we analyzed whether the proliferation of MCF-7 cells was altered by the expression of the exon 5 variant and found that the stimulatory effects of estrogen and growth inhibitory effects of tamoxifen and ICI 182780 were unchanged. We therefore conclude that expression of the variant alone is not sufficient to give rise to hormone independence or tamoxifen resistance of breast cancers.

Animals↗

PubMed1996

Dynamics of viral variants in HIV-1 Nef and specific cytotoxic T lymphocytes in vivo.

The vigorous CTL response directed against HIV is considered to be important in reducing HIV viral load, although it is unable to stop ongoing viral replication, which generates new antigenic variants. We analyzed the impact of sequential changes in five epitopes of HIV-1 Nef on CTL recognition in four stable patients. A high rate of variation was found, and in all these patients we could detect CTL specific for 32 out of 36 autologous viral variants occurring in 5 HLA-A2- or HLA-B7-restricted Nef epitopes at two time points. Two distinct patterns for dynamics of CTL responses to viral variation were observed: 1) temporary amplification of viral variants followed by expansion of variant-specific CTL, ultimately leading to the disappearance of 12 out of the 14 initial epitope variants within two years. A second set of viral variants that had replaced the initial ones could also stimulate specific CTL precursors in the context of the same or an alternative HLA molecule; and 2) persistence of 2 viral variants in relatively conserved epitopes despite specific CTL recognition. Therefore, a remarkable flexibility of the immune system allows constant adaptation of CTL to multiple HIV variants and thus elimination of HIV variant-producing cells in slow progressors.

Amino Acid Sequence↗

PubMed1998

Variants of papillary carcinoma of the thyroid: experience at Asir Central Hospital.

Papillary carcinoma of the thyroid is now further subclassifiable into its different variants. We report incidence, clinical behaviour and outcome of rare variants of papillary thyroid cancers at Asir Central Hospital, Saudi Arabia. These variants differ from each other not only on a morphometric basis, but also in clinical behaviour. Accordingly, we report our experience of different variants in a series of 35 papillary carcinomas. These cases were received in the surgical pathology laboratory of Asir Central Hospital from January 1987 to December 1994. We have reviewed clinical charts, microscopic slides and pathological reports of these carcinomas. The following results have been obtained: 20 cases were classical (usual) papillary thyroid carcinomas: seven were follicular variants; three were tall cell/ columnar variants; two were oxyphilic variants; and one was a diffuse sclerosing variant. There were two de-differentiated papillary carcinomas (anaplastic carcinomas with foci of well-differentiated papillary carcinomas). These variants were also correlated with clinical parameters such as age, sex and nationality of the patients, aggressiveness of the tumours, types of surgery required, and follow-up when available.

Adolescent↗

PubMed1976

Plasma alpha-L-fucosidase: presence of a low activity variant in some normal individuals.

The expression of a variant alpha-L-fucosidase has been determined in both plasma and leukocytes. This variant enzyme is characterized by unusually tow actuvity in plasma, an altered pH activity profile, and increased heat lability. Individuals possessing this low activity variant in plasma have usual levels of alpha-L-fucosidase activity in leukocytes. The leukocyte enzyme also shows increased heat lability and has an altered pH activity profile. Gel filtration of plasma alpha-L-fucosidase revealed both a high molecular weight form, alpha-L-fucosidase I, and a low molecular weight form, alpha-L-fucosidase II. Only alpha-L-fucosidase II could be detected upon gel filtration of the variant enzyme from plasma. Both control and variant leukocyte alpha-L-fucosidase revealed two peaks by gel filtration but the proportion of alpha-L-fucosidase I was reduced in the variant enzyme sample. Alpha-L-fucosidase II from both control and variant plasma and leukocyte samples was heat labile and possessed little activity at pH 4.0 Alpha-L-fucosidase I from control plasma and leukocytes was more stable to heating and possessed more activity at pH 4.0 than alpha-L-fucosidase II. In contrast, alpha-L-fucosidase I from the variant leukocyte sample was heat labile and had little activity at pH 4.0 thus resembling alpha-L-fucosidase II. These results suggest that the variant is the consequence of an altered allele which affects alpha-L-fucosidase expression in all tissues.

Adult↗

PubMed1995

Relationship of clone 4 estrogen receptor variant messenger RNA expression to some known prognostic variables in human breast cancer.

To gain insight into the possible biological role of variant estrogen receptor (ER) expression in human breast cancer, we have undertaken a study to determine if the expression of the clone 4 variant ER mRNA was associated with markers of either reduced endocrine sensitivity [i.e., progesterone receptor (PgR) negativity] or a poor prognosis (node positivity, large tumor size, and high percentage S-phase fraction). mRNA levels of clone 4 variant ER and wild-type (WT) ER were assayed by RNase protection assay in 106 breast cancer specimens. The tumors comprised two major groups: "good" prognosis and "poor" prognosis based on several conventional biological prognostic features. Each group was divided into three subgroups (ER+/PgR+, ER+/PgR-, and ER-/PgR-). WT and clone 4 variant ER mRNAs were undetected in ER-/PgR- tumors. We determined that clone 4 variant ER mRNA levels varied proportionately with WT mRNA levels, and regression analysis was used to determine if the amount of clone 4 variant ER mRNA relative to WT was associated with prognosis or PgR content. Significantly higher levels of clone 4 variant ER mRNA relative to WT were found in tumors with markers of poor prognosis compared to those with markers of good prognosis (P = 0.0004). Significantly higher levels of clone 4 variant ER mRNA relative to WT were found in PgR- tumors compared to PgR+ tumors (P = 0.011). Such data are consistent with an association of clone 4 variant ER mRNA expression with progression of human breast cancer from hormone dependence to independence.

Breast Neoplasms↗

PubMed2025

Extracting and calibrating evidence of variant pathogenicity from population biobank data.

Genomic medicine requires a robust evidence base of variant phenotypic impacts, which remains incomplete even in extensively studied genes with monogenic disease associations. Here, we evaluated the broad potential of using population cohort data to identify evidence that can be used in variant assessment. Across 41 genes related to 18 clinically actionable monogenic phenotypes, we calculated variant-level odds ratios of disease enrichment using data from 469,803 UK Biobank participants. We found significant differences in odds ratio values between ClinVar-labeled pathogenic and benign variants in 11 phenotypes, spanning both common and rare disorders. To facilitate clinical translation, we calibrated the strength of evidence provided by variant-level odds ratios to align with American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) interpretation guidelines (PS4 criterion) and found that odds ratios may reach "moderate," "strong," or "very strong" evidence, varying by phenotype and gene. Overall, we found that 2.6% (N = 12,350) of participants harbor a rare variant of uncertain significance (VUS) with at least moderate evidence of pathogenicity-an indication of potentially unrecognized disease risk. Finally, by incorporating computational and functional data alongside population-based odds ratios, we identified variants that met the criteria for clinical reclassification. Notably, using this approach, we identified that 12.4% of rare VUSs in LDLR seen in participants meet diagnostic criteria to be classified as likely pathogenic, demonstrating its potential to scale the reclassification of VUSs.

Humans↗

PubMed1984

The inactivation and reactivation of an expression-linked gene copy for a variant surface glycoprotein in Trypanosoma brucei.

We have previously shown that the gene for variant surface glycoprotein 118 of Trypanosoma brucei (strain 427) is activated by a duplicative transposition to a telomeric expression site. In chronically-infected animals, this expression-linked copy is lost when the 118 gene is replaced at the expression site by another variant surface glycoprotein gene. We show here that expression of the 118 gene can also be switched off without loss of the extra expression-linked copy. In two variants, called 1.8b and 1.8c, we find expression of the variant surface glycoprotein 1.8 gene, notwithstanding the continued presence of the 118 expression-linked copy. The 1.8 gene activated has a telomeric location, like the 118 expression-linked copy. In variant 1.8b, activation is accompanied by duplication of the 1.8 gene, resulting in an extra telomeric gene copy; in variant 1.8c it is not. Variants 1.8b and 1.8c both switch back preferentially to expression of the 118 gene. The 5'-flanking regions of the active, inactive and reactivated versions of the 118 expression-linked copy are indistinguishable by restriction mapping up to 28 kb. We conclude that there are at least two separate telomeric expression sites in our T. brucei strain. How these are switched on and off is unclear. The ability to retain expression-linked copies in inactive form may allow the trypanosome to re-programme the order in which variant surface glycoprotein genes are expressed.

Amino Acid Sequence↗

PubMed2026

INPP5K-related muscular dystrophy caused by a novel synonymous splicing variant in a Chinese patient: a case report.

Congenital muscular dystrophies (CMDs) are a genetically heterogeneous group of disorders. Variants in the INPP5K gene, which encodes a phosphoinositide phosphatase, are a rare cause of CMD. The condition is commonly associated with muscle weakness, early-onset cataracts, and intellectual disability, and prior reports have primarily identified missense, frameshift, or deletion variants. We describe the first Chinese case of INPP5K-related muscular dystrophy in a 28-year-old male with a mild phenotype, notably lacking intellectual disability. His presentation included bilateral cataracts at age 5 and adolescent onset limb girdle weakness. Muscle magnetic resonance imaging (MRI) revealed a characteristic pattern of selective fatty infiltration, with severe involvement of gluteal and thigh muscles and striking sparing of the rectus femoris, sartorius, and gracilis. Genetic analysis identified compound heterozygous novel INPP5K variants: a missense c.274C>T, p.(Arg92Cys) and a synonymous c.261G>A, p.(Lys87=) change. Functional studies confirmed the synonymous variant causes aberrant splicing (exon 3 skipping), leading to a frameshift and premature termination p.(Leu52SerfsTer49). According to American College of Medical Genetics and Genomics guidelines, the c.274C>T and c.261G>A variants were classified as likely pathogenic and pathogenic, respectively. This first report of a Chinese patient with INPP5K-related muscular dystrophy broadens both the genetic and clinical spectrum of the disorder. We identify the first disease-causing synonymous variant (via aberrant splicing) and a novel hypomorphic missense variant p.(Arg92Cys), the combination of which explains the attenuated phenotype lacking intellectual disability. Our case highlights the critical role of RNA analysis in diagnosing non-canonical variants and confirms the universal diagnostic relevance of the characteristic muscle MRI pattern.

Adult↗

PubMed1990

Magnesium deficiency detected by intravenous loading test in variant angina pectoris.

To study whether magnesium (Mg) deficiency is present in patients with variant angina, 24-hour Mg retention of low dose Mg (0.2 mEq/kg lean body weight) administered intravenously over 4 hours in 20 patients with variant angina was examined. No patient had received calcium antagonists before or during the study. All had attacks of chest pain associated with ST elevation on electrocardiograms. Twenty-one subjects without ischemic heart disease were studied as control subjects. Ten patients with variant angina were restudied 10 to 529 days (mean 235 +/- 30) after the treatment with calcium antagonists (diltiazem 120 to 240 or nifedipine 40 to 80 mg/day), which resulted in complete suppression of anginal attacks. The mean serum Mg concentrations in the patients with variant angina and the control subjects were 2.1 +/- 0.05 and 2.1 +/- 0.03 mg/dl, respectively (difference not significant). However, 24-hour Mg retention in the patients with variant angina was 60 +/- 5%, while that in the control subjects was 36 +/- 3% (p less than 0.001), suggesting that Mg deficiency is present in at least some patients with variant angina. The mean serum Mg concentrations before and after calcium antagonist treatment in 10 patients with variant angina were 2.1 +/- 0.09 and 2.1 +/- 0.07 mg/dl, respectively (difference not significant). However, 24-hour Mg retention decreased significantly (p less than 0.01) from 60 +/- 6 to 34 +/- 7% after the treatment. There is Mg deficiency in many patients with variant angina and it is corrected after treatment with calcium antagonists.

Adult↗

PubMed2025

Calibration of additional computational tools expands ClinGen recommendation options for variant classification with PP3/BP4 criteria.

PURPOSE: We previously developed an approach to calibrate computational tools for clinical variant classification, updating recommendations for the reliable use of variant impact predictors to provide evidence strength up to Strong. A new generation of tools using distinctive approaches has since been released, and these methods must be independently calibrated for clinical application. METHODS: Using our local posterior probability-based calibration and our established data set of ClinVar pathogenic and benign variants, we determined the strength of evidence provided by 3 new tools (AlphaMissense, ESM1b, and VARITY) and calibrated scores meeting each evidence strength. RESULTS: All 3 tools reached the Strong level of evidence for variant pathogenicity and Moderate for benignity, although sometimes for few variants. Compared with previously recommended tools, these yielded at best only modest improvements in the trade-offs between evidence strength and false-positive predictions. CONCLUSION: At calibrated thresholds, 3 new computational predictors provided evidence for variant pathogenicity at similar strength to the 4 previously recommended predictors (and comparable with functional assays for some variants). This calibration broadens the scope of computational tools for application in clinical variant classification. Their new approaches offer promise for future advancement of the field.

Humans↗

PubMed2025

Insulin receptor variants: Extending the traditional Mendelian spectrum.

PURPOSE: INSR encodes the insulin receptor, the essential entrainer of growth and metabolism to nutritional cues. INSR variants cause a spectrum of monogenic insulin resistance (IR) syndromes, namely, type A insulin resistance, Rabson-Mendenhall, and Donohue syndromes. However, to our knowledge, no large cohort studies focused on variant classification and its diagnostic value have been described. METHODS: This multicentric cohort study included 73 patients carrying INSR variants, referred for IR by 52 centers from 6 countries. Variants were classified using new bioinformatic tools relying on different prediction mechanisms and the American College of Medical Genetics and Genomics guidelines. RESULTS: Besides expanding the INSR mutational spectrum, this study suggested a semidominant inheritance in several Donohue/Rabson-Mendenhall syndrome families. Questioning strictly Mendelian inheritance, heterozygous loss-of-function (LoF) variants were mostly found in overweight patients, with a higher LoF frequency in IR patients than in the general population (odds ratio 5.77). Diagnostic challenges arose when trying to refine classification criteria for variants of uncertain significance. Among the variant effect predictors assessed, MISTIC and AlphaMissense outperformed REVEL. CONCLUSION: The spectrum of INSR-related disorders extends beyond traditional entities. Heterozygous INSR LoF variants may increase IR susceptibility. International collaboration and functional assays are needed to drive precision medicine forward.

Humans↗

PubMed2026

Dynamic case-control sampling for rapid estimation of vaccine effectiveness against an emerging infectious disease variant.

New SARS-CoV-2 variants arise frequently with different viral properties that can impact the effectiveness of the vaccines. Updating estimates of vaccine effectiveness (VE) in public health surveillance can be limited by the necessity of conducting a distinct study that entails analysis of prospective cohort data or using a test-negative design. We introduce a method for dynamically updating estimates of VE using data that accumulate in real time. Our method uses dynamic case-control sampling to estimate VE against a newly emerging variant relative to a previous variant. Dynamic case-control sampling is a technique that continuously updates VE estimates by comparing individuals infected with a newly emerging variant (defined as "cases") to those infected with a previously circulating variant (defined as "controls"). We use this estimate in combination with information about VE from the previous variant (these estimates are typically available from larger, traditional studies) to infer VE against the emerging variant. We demonstrate the utility of this method on the BA.1 and BA.2 sub-lineages of the Omicron variant. The method produces estimates of VE comparable to those produced using traditional methods, although with increased SE. The increase in error, however, is reasonable given a much smaller sample size than other studies, and error ranges of the estimates could be significantly improved by sequencing a larger proportion of identified cases. Our method, which assumes only a fraction of the new cases are being sequenced, can be applied by health departments using routinely collected data to produce timely, rigorous VE estimates to rapidly identify potential changes in VE.

Humans↗

PubMed1999

Variant angina is not associated with angiotensin I converting enzyme gene polymorphism but rather with smoking.

BACKGROUND: Angiotensin converting enzyme (ACE) perhaps plays roles in regulating coronary vasomotor tone by producing angiotensin II and degrading bradykinin. OBJECTIVES: We sought to investigate the role of ACE gene polymorphism in the pathogenesis of variant angina and to compare it with that of other clinical risk factors for male patients with variant angina and age-matched and sex-matched control subjects. METHODS: We studied 78 male patients with variant angina who exhibited spontaneous or provoked coronary spasms during coronary angiography and compared prevalences of ACE gene genotype (deletion D and insertion I) and other risk factors between this group of patients with variant angina and age-matched and sex-matched control subjects whose angiograms were normal and in whom the ergonovine test did not cause spasms (n = 80). RESULTS: Smokers were more prevalent in the group of patients with variant angina (P < 0.05). Genotype and allele prevalences of the group of patients with variant angina (0.14, 0.53 and 0.33 for DD, DI and II and 0.41 and 0.59 for D and I, respectively) were no different from those of the control group (0.16, 0.49 and 0.35 for DD, DI and II and 0.40 and 0.60 for D and I). Multiple logistic regression analysis showed that smoking was a significant risk factor for variant angina (odds ratio 2.61, 95% confidence interval 1.03-6.66) whereas ACE genotype was not. CONCLUSIONS: Variant angina is associated with an environmental factor, such as smoking, rather than a genetic factor, such as ACE gene polymorphism.

Aged↗

PubMed1985

Prostacyclin and variant angina.

Plasma levels of thromboxane B2 (TXB2) and 6-keto PGF1 alpha in the blood samples taken at the coronary sinus and ascending aorta from twenty-one Japanese patients with variant angina and twenty with effort angina were measured by radioimmunoassay, the objective being to search for the contribution of prostanoids in coronary spasm. The data were compared with data on thirteen subjects free from coronary artery diseases. In coronary sinus blood, plasma TXB2 in patients with effort angina exhibited statistically significant high levels, as compared with data in the controls. These with variant angina also had high levels, albeit without a statistically significant difference. Eight patients with variant angina and for whom the coronary angiogram showed more than 50% of narrowing had statistically significant high levels of TXB2, and the other thirteen with variant angina and normal coronaries or less than 50% of narrowing had the same plasma levels of TXB2 as the controls. In contrast to TXB2, the plasma levels of 6-keto PGF1 alpha in both coronary sinus and aortic blood of patients with variant angina were very low, as compared with normal controls. Statistically significant low levels of 6-keto PGF1 alpha were noted in the coronary sinus blood of patients with variant angina with normal coronaries and in the aortic blood of those with variant angina, as compared with data on the normal controls. Neither ergonovine test nor spontaneous attacks in patients with variant angina revealed characteristic changes in levels of TXB2 and 6-keto PGF1 alpha in the coronary sinus. These data suggest that high levels of TXB2 in patients with atherosclerotic coronaries may be one factor leading to spasm, while low levels of PGI2 may be a contributing factor.

6-Ketoprostaglandin F1 alpha↗

PubMed2024

Identification of a novel intronic variant in COL4A2 gene associated with fetal severe cerebral encephalomalacia and subdural hemorrhage.

BACKGROUND: Genetic variants in COL4A2 are less common than those of COL4A1 and their fetal clinical phenotype has not been well described to date. We present a fetus from China with an intronic variant in COL4A2 associated with a prenatal diagnosis of severe cerebral encephalomalacia and subdural hemorrhage. METHODS: Whole exome sequencing (WES) was applied to screen potential genetic causes. Bioinformatic analysis was performed to predict the pathogenicity of the variant. In in vitro experiment, the minigene assays were performed to assess the variant's effect. RESULTS: In this proband, we observed ventriculomegaly, subdural hemorrhage, and extensive encephalomalacia that initially suggested cerebral hypoxic-ischemic and/or hemorrhagic lesions. WES identified a de novo heterozygous variant c.549 + 5G > A in COL4A2 gene. This novel variant leads to the skipping of exon 8, which induces the loss of 24 native amino acids, resulting in a shortened COL4A2 protein (p.Pro161_Gly184del). CONCLUSION: Our study demonstrated that c.549 + 5G > A in COL4A2 gene is a disease-causing variant by aberrant splicing. This finding enriches the variant spectrum of COL4A2 gene, which not only improves the understanding of the fetal neurological disorders associated with hypoxic-ischemic and hemorrhagic lesions from a clinical perspective but also provides guidance on genetic diagnosis and counseling.

Female↗