Spectrum Of Variants Research Articles

The distribution and spectrum of thalassemia variants in GUIYANG region, southern China

Thalassemia is one of southern China’s most common inherited disorders. This retrospective study analyzed the results of thalassemia gene testing conducted on 20,478 individuals from January 1, 2019, to April 31, 2024 in the First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine. The cohort consisted of 19,733 females and 745 males, with 1401 individuals testing positive for thalassemia. Among the positive cases, 942 had α thalassemia, 431 had β thalassemia, and 25 had variants in both α and β thalassemia genes. Interestingly, a subgroup of individuals with thalassemia variants not previously documented in medical literature was identified. The study highlighted the prevalence of thalassemia among different ethnic groups, with individuals of Han ethnicity being the most affected. Geographical analysis revealed a concentration of cases in Guizhou Province, particularly in Guiyang city, Bijie, and Qiannan Prefecture. These findings provide valuable insights into the epidemiology of thalassemia in the region and the distribution of affected individuals.

Identification of Houge type of X-linked syndromic mental retardation caused by CNKSR2 truncated variants

BackgroundHouge type of X-linked syndromic mental retardation (MRXSHG) is a type of X-linked condition which is mainly manifested as delayed development, mental retardation, epilepsy that begins at an early age, and delayed language acquisition. MRXSHG is a serious disorder with CNKSR2 variant and at least 34 variants have been identified in MRXSHG patients. However, the genotype-phenotype correlation and variants characteristics of CNKSR2 need further investigation and improvement.MethodsTwo Chinese MRXSHG families were recruited, and their genetic causes were investigated using whole-exome sequencing (WES), Sanger sequencing, and bioinformatics analysis. To verify the impact of these variants, we used real-time PCR and minigenes consisting of exon 14, intron 14, and exon 15 from both the wild-type and the c.1658-3_1676del DNA sequences.ResultsIn this study, we reported two Chinese boys with MRXSHG and described some rare MRXSHG phenotypes, such as delayed bone age, slightly widened right fissure, and an underdeveloped right temporal lobe, characterized by reduced growth and volume compared to typical development. Two novel variants in CNKSR2 (c.1658-3_1676del and c.1102G > T, p.Gly368*) were identified in these cases. Minigenes results revealed that variant c.1658-3_1676del produced an aberrant spliceosome assembly.ConclusionsWe identified two novel CNKSR2 variants in MRXSHG families, expanding the variant spectrum of CNKSR2, enriching MRXSHG-related phenotypes, and contributing to genetic counseling for MRXSHG patients.

Genotype-Phenotype Spectrum of eyeGENE Patients With Familial Exudative Vitreoretinopathy: Novel Variants in Norrin/β-Catenin Signaling Pathway Genes.

To report the variants and genotype-phenotype correlations in patients with familial exudative vitreoretinopathy (FEVR) included in the eyeGENE database. A retrospective study was conducted in a cohort of 122 eyeGENE patients from 114 families with FEVR. Clinical details and genetic test results were provided by referring clinicians and clinical laboratories in the eyeGENE network, respectively. Genotype and phenotype information was reviewed, and reported variants were reclassified. Genetic test reports of 50 probands revealed 52 variants in the four genes of the Norrin/β-catenin signaling pathway: LRP5, FZD4, TSPAN12, and NDP. Following variant reclassification, 35 of the reported variants were interpreted as pathogenic or likely pathogenic (12 in LRP5, 11 in FZD4, seven in TSPAN12 and five in NDP), providing a conclusive test result for nearly one-third (32%) of the probands. Among the reported variants, 18 were novel (34.6%) and two-thirds were missense. Retinal detachment was reported less in patients with variants in TSPAN12 (P = 0.017). One-third of the patients (33.3%) with an FZD4 variant had asymmetric findings. In contrast, asymmetry was less pronounced in patients with variants in TSPAN12 (11.1%). This was one of the largest cohorts reviewed from North America, expanding the variant spectrum in FEVR. Among the eyeGENE FEVR patients, disease-associated variants in Norrin/β-catenin signaling pathway genes can explain one-third of the cohort. LRP5 and FZD4 variants were the most common. The genotype-phenotype correlations supported the phenotypic variability in FEVR.

Chimeric CYP21A1P/CYP21A2 Genes in 21-Hydroxylase Deficiency Detected by Long-Read Sequencing and Phenotypes Correlation.

21-Hydroxylase deficiency (21-OHD) is caused by pathogenic variants in CYP21A2. High homology between CYP21A2 and its pseudogene CYP21A1P causes mismatches, leading to deletions and CYP21A1P/CYP21A2 chimeras. To detect chimeric CYP21A1P/CYP21A2 in 21-OHD patients using long-read sequencing (LRS) and analyze genotype-phenotype correlations. From 2015 to 2023, 869 21-OHD patients were enrolled at Peking Union Medical College Hospital, with 113 identified harboring CYP21A2 large deletion. Long-range PCR and LRS were used to identify the types of CYP21A1P/CYP21A2 chimeric. Haplotype analysis explored founder effects, and in vitro assays assessed the functional impact of novel mutations. Clinical data were retrospectively collected and patients were classified into 4 groups based on genotypes and residual enzyme activity to study genotype-phenotype correlations. Ten types of chimeric CYP21A1P/CYP21A2 genes were identified across 119 alleles, including a novel type, CH-10. The most common, CH-1, accounted for 50.4% of all types. Haplotype analysis of 24 SNPs within CYP21A1P/CYP21A2 CH-1 revealed 25 haplotypes, with haplotype 11 being the most prevalent. Variants p.L100P and p.L301V of CYP21A2 showed enzyme activities of 1.36 ± 0.44% or 1.63 ± 0.19% for 17-hydroxyprogesterone to 11-deoxycortisol, and 1.36 ± 0.58% or 3.99 ± 1.09% for progesterone to 11-deoxycorticosterone, respectively, linked to the simple virilizing type. Genotype-phenotype consistency rates were 78.6% to 84% across the 4 groups. LRS is a comprehensive genetic testing method for 21-OHD patients, effectively detecting both CYP21A2 gene variants and CYP21A1P/CYP21A2 chimeric gene types. This study expands the CYP21A2 variant spectrum by identifying a novel chimera. Haplotype analysis revealed diverse haplotypes for each chimeric gene type, suggesting the absence of a common founder effect. The strong genotype-phenotype correlation aids genetic counseling and supports personalized treatment.

Gene Variant Spectrum in Probands With Familial Exudative Vitreoretinopathy Using an Expanded Panel.

To investigate the gene variant spectrum in patients with familial exudative vitreoretinopathy (FEVR). Probands clinically diagnosed with FEVR and their relatives were enrolled and clinical information and DNA collected. An expanded FEVR panel was used, including six recognized FEVR genes (FZD4, NDP, LRP5, TSPAN12, ZNF408, and CTNNB1) and 19 genes previously associated with ocular features overlapping FEVR (FEVR-associated genes). Variants identified using targeted next-generation sequencing and/or Sanger sequencing were analyzed and classified using the American College of Medical Genetics and Clinical Genome Resource Sequence Variant Interpretation (ClinGen SVI) working group recommendations to detect disease-causing variants (DCVs). Analyses of data from a cohort of 94 probands provided a molecular diagnosis for 39 (41.5%) probands: 34 (87.2%) had a single DCV, whereas 5 (12.8%) harbored more than 1 DCV. Of 41 total DCVs in solved probands, 33 (80.5%) were in 4 of the 6 recognized genes, LRP5, FZD4, TSPAN12, and NDP, whereas 8 were found in FEVR-associated genes, 6 in KIF11, and 2 (LAMA1 and DOCK6) each in association with a KIF11 DCV. Reanalyzing variants using the latest criteria impacted the variant classification in five probands (5.3%), changing variants that were once deemed likely pathogenic to variants of uncertain significance. The expanded FEVR gene panel detected DCVs in nearly one-half of our cohort. Including the criteria used in classification will improve transparency of variant calls as more data become available. Four FEVR genes account for most cases, and the role of rare FEVR genes and candidate genes requires further study.

A Cryptic CBFB Deletion-Inversion Expands the Mutational Spectrum of Variants Associated With Cleidocranial Dysplasia.

CBFB encodes the core-binding factor β subunit, a small protein which heterodimerises with RUNX1-3 and activates transcription of genes important in bone development. Recently, five families with cleidocranial dysplasia (CCD) were identified harbouring presumed loss of function variants in CBFB. Prompted by a multidisciplinary team review of an affected mother and daughter from the 100 000 Genomes Project with genetically unsolved CCD, we inspected read alignments and identified a deletion-inversion-deletion that removes the first two exons of CBFB. This cryptic variant comprised interlinked deletions of 1310 bp and 1935 bp and had remained undetected by both array-CGH and the Canvas algorithm. The rearrangement was likely mediated by a palindromic AluSx repeat < 1 kb from the transcriptional start site. Due to high GC content and repeats, reduced read depth is observed at one of the breakpoints. Although the clinical presentation of CBFB-related CCD appears to be very similar to RUNX2-related CCD, our patients were of normal stature. The mild developmental delay observed in previously reported cases of CBFB-related CCD was not observed. In conclusion, our data strengthens the evidence linking aberrations of the core-binding factor complex to CCD and extends the mutational spectrum of pathogenic variants.

A Novel Compound Heterozygous Variant in the ABHD12 Gene Cause PHARC Syndrome in a Chinese Family: The Proband Presenting New Genotype and Phenotype.

PHARC syndrome, a rare autosomal recessive neurodegenerative disorder caused by mutations in the ABHD12 gene, is characterized by demyelinating polyneuropathy, hearing loss, ataxia, retinitis pigmentosa (RP), and early-onset cataracts. If patients are first diagnosed in the ophthalmology department, they are easily misdiagnosed as having RP or Usher syndrome. This study aimed to identify the genetic etiology and determine the clinical diagnosis of a Chinese family with suspected PHARC syndrome. Comprehensive ophthalmic examinations and systemic evaluations were conducted to confirm the phenotype. The genotype was identified through Whole Exome Sequencing (WES), and the current literature was reviewed understand better manifestations of PHARC syndrome related to pathogenic variants. The principal symptoms of the proband comprised profound sensorineural hearing loss since childhood, severe visual impairment, congenital cataracts, cone-rod dystrophy, and ataxia. WES revealed that the proband carried a compound heterozygous variant in the ABHD12 gene: M1, a known nonsense variation c.477G > A (p.Trp159Ter); and M2, a novel copy number variant with a deletion of approximately 18.10 Kbp in chromosome 20p11.21 (seq[GRCh38]del(20) (p11.21)chr20:g. 25302218_25320318del), covering exons 4-12 of the ABHD12 gene. The literature review indicated that there were 65 patients with PHARC from 30 different families. All clinical information of the described patients with PHARC syndrome and all known mutations associated with the disease to date were compiled. This study expands the spectrum of pathogenic variants and phenotype for PHARC syndrome and suggests genetic testing is necessary for a definitive diagnosis of PHARC syndrome.

A Spectrum of Pathogenic Variants in the LAMA2 Gene in the Russian Federation

A Spectrum of Pathogenic Variants in the LAMA2 Gene in the Russian Federation

Identifying novel heterozygous PI4KA variants in fetal abnormalities

BackgroundThe clinical manifestations of PI4KA-related disorders are characterized by considerable variability, predominantly featuring neurological impairments, gastrointestinal symptoms, and a combined immunodeficiency. The aim of this study was to delineate the novel spectrum of PI4KA variants detected prenatally and to assess their influence on fetal development.MethodsA thorough fetal ultrasound screening was conducted, supplemented by both antenatal and post-abortion magnetic resonance imaging (MRI) studies. Novel PI4KA variants were detected through clinical Whole exon sequencing (WES) and validated by Sanger sequencing. The functional consequences of these variants were evaluated using bioinformatics tools. The effects of the identified variants on splicing were analyzed through minigene splicing assays. Subsequently, both wild-type and mutant PI4KA protein fragments were purified, and their enzymatic activities were quantitatively assessed.ResultsUltrasound imaging, MRI scans revealed a dilated small intestine with an obstruction. Compound heterozygous variants (NM_058004.3: c.2802_2863-40del and c.2819 C > T, p.Ala940Val) were identified in the PI4KA of the affected fetus through clinical trio-WES. Both variants were predicted deleterious. The PI4KA variant c.2802_2863-40del resulted in the production of three distinct mRNA isoforms. The PI4KA variant c.2819 C > T (p.Ala940Val) significantly reduced the enzyme activity.ConclusionsThis study extended the mutational spectrum of PI4KA and may provide guidance for genetic counseling. Functional studies confirmed that the identified variant induces alterations in RNA splicing and impairs enzyme activity.

Evaluation of Genomic Surveillance of SARS-CoV-2 Virus Isolates and Comparison of Mutational Spectrum of Variants in Bangladesh

The SARS-CoV-2-induced disease, COVID-19, remains a worldwide public health concern due to its high rate of transmission, even in vaccinated and previously infected people. In the endemic state, it continues to cause significant pathology. To elu- cidate the viral mutational changes and screen the emergence of new variants of concern, we conducted this study in Bangladesh. The viral RNA genomes extracted from 25 ran- domly collected samples of COVID-19-positive patients from March 2021 to February 2022 were sequenced using Illumina COVID Seq protocol and genomic data processing, as well as evaluations performed in DRAGEN COVID Lineage software. In this study, the percentage of Delta, Omicron, and Mauritius variants identified were 88%, 8%, and 4%, respectively. All of the 25 samples had 23,403 A&gt;G (D614G, S gene), 3037 C&gt;T (nsp3), and 14,408 C&gt;T (nsp12) mutations, where 23,403 A&gt;G was responsible for increased transmis- sion. Omicron had the highest number of unique mutations in the spike protein (i.e., sub- stitutions, deletions, and insertions), which may explain its higher transmissibility and immune-evading ability than Delta. A total of 779 mutations were identified, where 691 substitutions, 85 deletions, and 3 insertion mutations were observed. To sum up, our study will enrich the genomic database of SARS-CoV-2, aiding in treatment strategies along with understanding the virus’s preferences in both mutation type and mutation site for predicting newly emerged viruses’ survival strategies and thus for preparing to coun- teract them.

Genotype-phenotype correlations for 17 Chinese families with inherited retinal dystrophies due to homozygous variants

In this study, patients with inherited retinal dystrophies (IRDs) who visited Ningxia Eye Hospital from January 2015 to September 2023 were analyzed. Through Whole Exome Sequencing (WES) and Sanger verification, 17 probands carrying homozygous variants were detected. The association between the genotype and clinical phenotype of patients with homozygous variants was analyzed. Among all the patients, 3 patients (17.6%) had a family history of consanguineous marriage, and the onset age of 5 patients(29.4%) was less than 10 years. According to 12 patients (70.6% ), they had the best corrected visual acuity (monocular) < 0.3. 3 were blind, 9 with moderate to severe visual impairment, and 2 with mild visual impairment. 16 homozygous variants were detected in 9 different genes, of which 7 were novel homozygous variants, including frameshift variants, missense variants, and a copy number variant. These variants are related to clinical phenotypes such as Usher syndrome type II (USH2), Stargardt disease (STGD), retinitis pigmentosa (RP), Leber congenital amaurosis (LCA), and Bardet-Biedl syndrome (BBS) respectively. The results of the study indicate that more than 80% of persons with homozygous variant originated from non-consanguineous families, emphasizing the significance of genetic screening for individuals who lack a family history of consanguineous marriage and no obvious clinical phenotypes, but who may carry genetic pathogenic variants for genetic diseases. Furthermore, by analyzing the genotypes and clinical phenotypes of IRD patients from these 17 Chinese families, we have expanded the spectrum of variants in known pathogenic genes for IRDs and the range of clinical phenotypes associated with variants in these genes. We have identified couples at high risk of having affected offspring and individuals with moderate to severe IRDs, providing a basis for genetic counseling, reproductive decision-making, disease prevention, and management. Our findings highlight the association between homozygous variants and more severe clinical phenotypes within these families, thus laying the groundwork for future genetic screening and intervention strategies.

Exploring the Familial Phenotypic Variability Associated With TTN Truncating Variants in Cardiomyopathies: Variant Spectrum, Genotype-Phenotype Correlation andConsequences in Genetic Counseling.

Titin truncating variants (TTNtv) are the main genetic cause of dilated cardiomyopathies (DCMs). The phenotype and prognosis of probands have been evaluated in several large cohorts. However, few data are available on intrafamilial expressivity. To evaluate the phenotypical variability, we selected probands and family members carrying a unique TTN variant and recorded cardiac and genetic information. The cohort included 332 probands (314 TTNtv probands and 18 probands with in silico predicted in-frame exon skipping probands) and 191 relatives of TTNtv probands including 98 affected family members. Within TTNtv families, 96% of the affected relatives presented the same cardiomyopathy subtype as the proband, and 60% shared severity criteria (heart transplantation, implantable cardioverter-defibrillator, personal sudden death). Furthermore, we reported 18 probands that carry predicted in-frame exon skipping variants; they presented DCM (84%) as TTNtv patients but lower rate of rhythm disorders (0% vs. 29% respectively). In this work, we extend the genetic spectrum of TTNtv associated with DCM and show that within a family, and the cardiomyopathy phenotype is homogenous but the expressivity could vary. Such results are helpful for appropriate genetic counseling to better predict and manage the phenotype of mutation carriers.

An X-Linked Ataxia Syndrome in a Family with Hearing Loss Associated with a Novel Variant in the BCAP31 Gene.

Pathogenic variants in B-cell receptor-associated protein (BCAP31) are associated with X-linked, deafness, dystonia and cerebral hypomyelination (DDCH) syndrome. DDCH is congenital and non-progressive, featuring severe intellectual disability (ID), variable dysmorphism, and sometimes associated with shortened survival. BCAP31 encodes one of the most abundant chaperones, with several functions including acting as a negative regulator of endoplasmic reticulum (ER) calcium ion (Ca2+) concentration. Here, we characterize an X-linked syndrome, its underlying genotype, and a functional evaluation of the identified candidate genetic variant. Evaluation of motor features, neuroimaging studies, neurophysiological, and cognitive tests. Whole exome sequencing (WES) was applied, a plasmid encoding BCAP31 with and without a candidate variant was transfected into SH-SY5Y cells to assess subcellular location and to measure Ca2+ levels in the cytoplasm. Adult-onset ataxia, cognitive impairment, and hearing loss leading to deafness are the predominant features. Reduced penetrance, slow progression with preserved ability to walk in advance age, and universal cerebellar atrophy are other features for this syndrome. This condition is associated with the new variant c.22G>A (V8I) in BCAP31 at Xq28. The subcellular location of the V8I BCAP31 protein was not altered but caused significant elevation of cytosolic Ca2+. Our findings expand the spectrum of variants in BCAP31 from neurodevelopmental syndromes to include a progressive neurodegenerative disease with variable expressivity. This is the first time ataxia is described in association with a BCAP31 variant and functional evidence of pathogenicity is provided. Additional BCAP31 cases featuring ataxia are needed to establish an association. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Updates on the molecular spectrum of MEFV variants in lebanese patients with Familial Mediterranean Fever.

Familial Mediterranean Fever (FMF) is a hereditary autoinflammatory disorder, particularly present in the Mediterranean populations, and associated with pathogenic variants in the MEFV gene. This study aims to investigate the distribution of MEFV variants in a large cohort of Lebanese patients, and to explore the genotype-phenotype correlation among affected individuals. A retrospective analysis was conducted on 3,167 patients referred for MEFV sequencing at the Medical Genetics and Genomics Center(CGGM) at Saint-Joseph University of Beirut-Lebanon, from 2006 to 2023. Sanger sequencing was used to detect MEFV variants, focusing initially on hot-spot exons. Among the 3,167 patients, 46.73% (N = 1,480) carried at least one MEFV variant. The most common variants detected were M694V and V726A, both found in 28.98% of cases, followed by E148Q(27.83%) and M694I(13.98%). Moreover, Shiites and Sunni Muslims, and individuals from South and North Lebanon exhibited the highest frequency of variants. Interestingly, family history was found to be significantly higher in patients having two MEFV variants than those with one variant (p = 0.0026). The most commonly reported symptoms were fever(78%), abdominal pain(88%), joint pain(65%), and thoracic pain(46%). The genotype-phenotype correlation analysis revealed a more severe phenotype in patients carrying the M694V or V726A mutations compared to those with the homozygous E148Q genotype. This study, the largest in Lebanon, highlights the high prevalence of MEFV variants, particularly M694V and V726A, in FMF patients. Our data provide valuable insights into the genetic landscape of FMF in Lebanon and emphasize the importance of early genetic screening for a better disease management and genetic counselling.

Genetic Structure of Hereditary Forms of Diabetes Mellitus in Russia.

Analyzing the genetic architecture of hereditary forms of diabetes in different populations is a critical step toward optimizing diagnostic and preventive algorithms. This requires consideration of regional and population-specific characteristics, including the spectrum and frequency of pathogenic variants in targeted genes. As part of this study, we used a custom-designed NGS panel to screen for mutations in 28 genes associated with the pathogenesis of hereditary diabetes mellitus in 506 unrelated patients from Russia. The study identified 180 pathogenic or likely pathogenic variants across 13 genes (GCK, HNF1A, HNF1B, HNF4A, ABCC8, INS, INSR, KCNJ11, PAX4, PDX1, ZFP57, BLK, WFS1), representing 46.44% of the analyzed cohort (235 individuals). The glucokinase gene (GCK) had the highest number of identified variants, with 111 variants detected in 161 patients, 20 of which were identified for the first time. In the tissue-specific transcription factor genes HNF1A, HNF4A, and HNF1B, 34 variants were found in 38 patients, including 13 that were previously unreported. Seventeen variants were identified in the ABCC8 gene, which encodes the ATP-binding cassette transporter 8 of subfamily C, each found in a different patient; four of these were novel discoveries. Nine pathogenic or likely pathogenic variants were identified in the insulin gene (INS) and its receptor gene (INSR), including four previously unreported variants. Additionally, we identified 10 previously unreported variants in six other genes among 11 patients. Variants in the genes GCK, HNF1A, HNF1B, HNF4A, ABCC8, INS, and INSR were the main contributors to the genetic pathogenesis of hereditary diabetes mellitus in the Russian cohort. These findings enhance our understanding of the molecular mechanisms underlying the disease and provide a solid basis for future studies aimed at improving diagnostic accuracy and advancing personalized therapeutic strategies. This knowledge provides a foundation for developing region-specific genetic testing algorithms and personalized therapeutic strategies, which are critical for future initiatives in precision medicine.

Expanding the Molecular Spectrum of MMP21 Missense Variants: Clinical Insights and Literature Review.

The failure of physiological left-right (LR) patterning, a critical embryological process responsible for establishing the asymmetric positioning of internal organs, leads to a spectrum of congenital abnormalities characterized by laterality defects, collectively known as "heterotaxy". MMP21 biallelic variants have recently been associated with heterotaxy syndrome and congenital heart defects (CHD). However, the genotype-phenotype correlations and the underlying pathogenic mechanisms remain poorly understood. Patients harboring biallelic MMP21 missense variants who underwent diagnostic genetic testing for CHD or heterotaxy were recruited at the Institute for Maternal and Child Health-I.R.C.C.S. "Burlo Garofolo". Additionally, a literature review on MMP21 missense variants was conducted, and clinical data from reported patients, along with molecular data from in silico and modeling tools, were collected. A total of 18 MMP21 missense variants were reported in 26 patients, with the majority exhibiting CHD (94%) and variable extra-cardiac manifestations (64%). In our cohort, through Whole-Exome Sequencing (WES) analysis, the missense p.(Met301Ile) variant was identified in two unrelated patients, who both presented with heterotaxy syndrome. Our comprehensive analysis of MMP21 missense variants supports the pathogenic role of the p.(Met301Ile) variant and provides significant insights into the disease pathogenesis. Specifically, missense variants are distributed throughout the gene without clustering in specific regions, and phenotype comparisons between patients carrying missense variants in compound heterozygosity or homozygosity do not reveal significant differences. These findings may suggest a potential loss-of-function mechanism for MMP21 missense variants, especially those located in the catalytic domain, and highlight their critical role in the pathogenesis of heterotaxy syndrome.

Functional study of three cases with novel TBX19 variants.

Congenital isolated adrenocorticotropic hormone deficiency (CIAD) is an autosomal recessive disorder. This study identifies novel TBX19 variants for CIAD patients, explores its possible effect mechanism at the structural, functional and protein levels, and guides clinicians better understand the condition. The clinical characteristics of three CIAD children were summarized. Multiple sequence alignment was performed and five algorithms, PROVEA, PolyPhen2, Mutation Taster, FATHMM, and I Mutant2.0, were used for the pathogenicity prediction. In addition, the three-dimensional protein structure of wild-type TBX19 was generated by Alphafold 3 and its variants were shown using PyMOL. Furthermore, immunoblotting analysis was applied to examine changes in the protein levels and the luciferase reporter assay was performed to further investigate the effects of TBX19 and its variants on pro-opiomelanocortin (POMC) transcriptional activity. We describe three Chinese patients with CIAD caused by TBX19 variants. The TBX19 variant, c.856C>T (p.R286*) was classified as pathogenic according to ACMG, whereas the other four variants, c.377C>T (p.P126L), c.602A>T (p.E201V), c.401A>G (p.H134R) and c.299G>A (p.R100H) were predicted to be disease-causing. Variants lead to alter interactions, conformational changes in proteins or truncate protein. TBX19 and PITX1 cooperated, resulting in a strong synergistic activation effect on POMC transcriptional expression. A functional study showed that the variants in our study result in a significant suppression of POMC transcriptional activity compared to wild-type TBX19. Our study identifies five TBX19 loss-of-function variants, two of which are novel and that provides new perspectives into the pathophysiological mechanism and expands the variant spectrum in IAD.

Lethal Phenotype and Expansion of the Clinical Spectrum of Biallelic Loss of Function Variant in SENP7 Gene Unveiled by Whole Exome Sequencing

ABSTRACTSUMOylation involves covalent attachment of small ubiquitin‐like modifier (SUMO) proteins to specific lysine residues on target proteins and regulates various aspects of their function. Sentrin‐specific proteases (SENPs) are key players in both the conjugation reaction of SUMO proteins to their targets and the subsequent deconjugation of SUMO‐conjugated substrates. Here, we provide the first comprehensive prenatal description of a lethal syndrome linked to a novel homozygous stop‐gain variant in SENP7 c.745C&gt;T; p.(Arg249*) in a consanguineous Egyptian family with a history of three fetal deaths, all presenting with multiple congenital anomalies. Similar anomalies were observed through ultrasound assessment of the current fetus, including arthrogryposis multiplex congenita, CNS malformations, congenital heart disease, and renal anomalies. Singleton exome sequencing (ES) of fetal DNA revealed a SENP7 variant allele, which results in a premature termination codon, and the mutant mRNA is predicted to be degraded by nonsense‐mediated decay (NMD). This leads to impaired gene function, particularly disrupting SENP7's isopeptidase activity in deconjugating polySUMO chains. Our findings broaden the molecular spectrum of SENP7 variants and emphasize their essential role in the development of the nervous, musculoskeletal, cardiovascular, and renal systems. This study offers new insights into the genotype–phenotype correlations observed in lethal congenital contracture syndromes and severe embryological abnormalities.

Genotypic Spectrum in a Cohort of Sri Lankan Patients With Homocystinuria.

Homocystinuria due to cystathionine beta-synthase (CBS) deficiency is a rare metabolic disorder inherited as an autosomal recessive trait. Spectrum of genetic variants in CBS gene and their correlation with the phenotypes of homocystinuria in Sri Lankan patients have not been reported to date. The objective of this study was to identify the genotypes and genotype-phenotype correlations in a cohort of Sri Lankan patients with homocystinuria due to CBS deficiency. We determined the variants in CBS gene in 14 Sri Lankan patients with homocystinuria, from 9 unrelated families. The clinical features and the biochemical response to pyridoxine were studied for further correlations. Among the 14 patients, the common clinical features were ectopia lentis (100%), intellectual disability (92%) and marfanoid features (78%) at presentation while three of them had developed osteoporosis (21%). Median age at diagnosis was 8 years (range 2-12). Three pathogenic variants (c.1006C>T, c.785C>T and c.19del) and two likely pathogenic variants (c.869C>T, c.772G>A) in CBS gene were identified. Thirteen patients with homozygous genotypes were non-responsive to pyridoxine while the only patient with the compound heterozygous genotype (c.869C>T/c.772G>A) responded to pyridoxine treatment. The genotypic spectrum observed in Sri Lankan patients is unique and mostly associated with pyridoxine non-responsiveness. The majority of the patients were identified clinically at a later stage of the disease due to lack of a screening programme in the country. Therefore, it is important to improve the awareness of the disease among the clinicians in the interest of early diagnosis and early commencement of metabolic treatment.

Alström syndrome: A rare cause of dilated cardiomyopathy in five Chinese children.

The ALMS1 gene is predominantly localized to cilia, particularly in the photoreceptor cells of the retina, auditory neurons, kidneys, and other ciliated structures. Pathogenic mutations in this gene cause Alstrom syndrome (AS), which is characterized by dilated cardiomyopathy, retinal degeneration, neurodeafness, and centripetal obesity. However, the genetic mechanism of the ALMS1 gene remains unclear. This study reports five cases of Chinese children with heterozygous variants in the ALMS1 gene, aiming to expand the genetic map of AS and provide insights into its pathogenesis. Whole exome sequencing (WES) was performed on 128 children diagnosed with DCM. ALMS1 variants were identified, and their pathogenicity and conservation were analyzed using bioinformatics tools. A retrospective analysis of genotypephenotype associations was also conducted in conjunction with previously reported cases. A total of eleven variants were identified in the five patients, including seven nonsense variants c.2035C > T(p.R679*), c.10825C > T(p.(R3609*)), c.5230C > T(p.(Q1744*)), c.3008C > A(p.(S1003*)), c.11686delG(p.(V3896*)), c.2090C > A(p.(S697*)), c.12373C > T(p.(Q4125*)), two frameshift variants c.10383delT(p.(I3461fs*48)), c.1685_c.1686insCAG(p.(D563fs*4)), and two missense variants c.12163C > G(p.(R4055G)) and c.7867G > A(p.A2623T). Cardiac ultrasound revealed improvements in left ventricular ejection fraction (LVEF) following treatment, although no significant change in nystagmus was observed. This study expands the genetic spectrum of ALMS1 gene variants and reinforces their pathogenicity through bioinformatics analysis. Additionally, we emphasize the importance of comprehensive cardiac evaluation and genetic testing in patients with DCM presenting with nystagmus.