Purpose:To diagnose and perform preimplantation genetic testing for monogenic disorders (PGT-M) in a Chinese family affected by Cornelia de Lange syndrome type 5, resulting from a microdeletion in Xq13.1q13.2 truncating the HDAC8 gene characterized by low-level gonadal mosaicism. Patients and Methods:A de novo copy number variation (CNV) was identified through chromosomal microarray analysis and whole exome sequencing in a family with two unsuccessful pregnancies, indicating germline mosaicism. The CNV was validated via real-time quantitative PCR. Whole-genome low-coverage mate-pair sequencing was conducted on female peripheral blood to exclude chromosomal abnormalities. Long-PCR amplified the deleted fragment, utilizing primers designed nearby breakpoints identified through chromosomal microarray analysis. Oxford Nanopore Technology sequencing pinpointed specific breakpoint positions. Droplet-digital PCR (ddPCR) confirmed germline mosaicism in ovarian samples. Results:A female patient, suspected of harboring a de novo microdeletion at Xq13.1q13.2 exhibiting gonadal mosaicism, along with her husband, participated in this study. The diagnoses of the 172.3 kb microdeletion at Xq13.1q13.2 as low-level gonadal mosaicism was corroborated through nanopore sequencing and ddPCR. We constructed the high-risk haplotype using the affected products of conception as the phasing reference, and performed PGT-M based on SNP haplotype linkage analysis, finally achieving a healthy live birth in February 2023. Conclusion:Our findings underscore the efficacy of PGT-M employing haplotype linkage analysis for CNVs less than 1 Mb, even within cases involving gonadal mosaicism. We present methodologies to address microdeletions associated with gonadal mosaicism utilizing next-generation sequencing, microarray, nanopore sequencing and ddPCR techniques. Our results advocate for an expansion of PGT-M based on haplotype linkage analysis for families with minor pathogenic CNVs.
Lulu Meng,1,* Yan Wang,1,* Junqiang Zhang,2,* Ran Zhou,1 Xingxing Wang,3 Fengchang Qiao,1 Qinxin Zhang,1 Cheng Wan,3 Shujing Jiao,3 Ping Hu,1 Zhengfeng Xu11Department of Prenatal Diagnosis, Women’s Hospital of Nanjing Medical University (Nanjing Women and Children’s Healthcare Hospital), Nanjing, Jiangsu, People’s Republic of China; 2State Key Laboratory of Reproductive Medicine, Department of Reproduction Medicine, Women’s Hospital of Nanjing Medical University (Nanjing Women and Children’s Healthcare Hospital), Nanjing, Jiangsu, People’s Republic of China; 3Department of Research and Development, Yikon Genomics Co. Ltd, Suzhou, Jiangsu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ping Hu, Department of Prenatal Diagnosis, Women’s Hospital of Nanjing Medical University (Nanjing Women and Children’s Healthcare Hospital), 123 Tianfei Alley, Mochou Road, Nanjing, Jiangsu, 210004, People’s Republic of China, Email njfybjyhuping@163.com Zhengfeng Xu, Department of Prenatal Diagnosis, Women’s Hospital of Nanjing Medical University (Nanjing Women and Children’s Healthcare Hospital), 123 Tianfei Alley, Mochou Road, Nanjing, Jiangsu, 210004, People’s Republic of China, Email zhengfengxu@njmu.edu.cnPurpose: To diagnose and perform preimplantation genetic testing for monogenic disorders (PGT-M) in a Chinese family affected by Cornelia de Lange syndrome type 5, resulting from a microdeletion in Xq13.1q13.2 truncating the HDAC8 gene characterized by low-level gonadal mosaicism.Patients and Methods: A de novo copy number variation (CNV) was identified through chromosomal microarray analysis and whole exome sequencing in a family with two unsuccessful pregnancies, indicating germline mosaicism. The CNV was validated via real-time quantitative PCR. Whole-genome low-coverage mate-pair sequencing was conducted on female peripheral blood to exclude chromosomal abnormalities. Long-PCR amplified the deleted fragment, utilizing primers designed nearby breakpoints identified through chromosomal microarray analysis. Oxford Nanopore Technology sequencing pinpointed specific breakpoint positions. Droplet-digital PCR (ddPCR) confirmed germline mosaicism in ovarian samples.Results: A female patient, suspected of harboring a de novo microdeletion at Xq13.1q13.2 exhibiting gonadal mosaicism, along with her husband, participated in this study. The diagnoses of the 172.3 kb microdeletion at Xq13.1q13.2 as low-level gonadal mosaicism was corroborated through nanopore sequencing and ddPCR. We constructed the high-risk haplotype using the affected products of conception as the phasing reference, and performed PGT-M based on SNP haplotype linkage analysis, finally achieving a healthy live birth in February 2023.Conclusion: Our findings underscore the efficacy of PGT-M employing haplotype linkage analysis for CNVs less than 1 Mb, even within cases involving gonadal mosaicism. We present methodologies to address microdeletions associated with gonadal mosaicism utilizing next-generation sequencing, microarray, nanopore sequencing and ddPCR techniques. Our results advocate for an expansion of PGT-M based on haplotype linkage analysis for families with minor pathogenic CNVs.Keywords: preimplantation genetic testing for monogenic disease, PGT-M, Cornelia de Lange syndrome, CdLS, low-level gonadal mosaicism, nanopore sequencing, droplet-digital PCR
Purpose:The prevalence of consanguineous marriages remains high in several regions worldwide, particularly the Middle East and South Asia, with a reported rate of 58%. However, the prevalence and genetic characteristics of consanguineous marriages in Mongolia are not well studied. This study aimed to estimate the frequency of consanguineous marriages in selected Mongolian populations, using genealogical and short tandem repeat (STR) analyses. Patients and Methods:This cross-sectional study was conducted at the Institute of Biomedicine at the Mongolian National University of Medical Sciences. A total of 574 individuals from 185 families across 43 soums in three provinces (X1, X2, and X3) were included. Genealogical analysis was used to construct pedigree-based consanguinity profiles, and STR analysis was performed to validate biological relatedness in selected families. Results:Seventeen families were consanguineous, with a mean inbreeding coefficient of 0.089 ± 0.136, whereas 42 families were classified as suspected consanguinity. Among the confirmed cases, seven families with complete biological samples were further analyzed using STR markers, of which five showed molecular evidence of consanguinity (probabilities, 76.18-98.84%). The STR analysis of 29 families classified as suspected or non-consanguineous identified 13 families as non-consanguineous and 10 families showing possible or indeterminate relatedness. Notably, six families initially classified as suspected or non-consanguineous demonstrated molecular evidence of consanguinity (probabilities, 70.75-99.85%). Genetic diversity analysis revealed reduced heterozygosity in offspring from consanguineous families (expected heterozygosity [HE] = 0.7580, observed heterozygosity[HO] = 0.7045) compared with offspring from non-consanguineous families (HE = 0.7858, HO = 0.8110), with a significant reduction in HO (p = 0.0009). Conclusion:This study demonstrates the value of integrating genealogical and STR-based molecular approaches for the assessment of consanguinity in Mongolia. Molecular analyses identified consanguineous relationships that were not evident from pedigree information alone and revealed reduced genetic diversity among offspring from consanguineous families. These findings provide important baseline data for understanding the genetic consequences of consanguinity in the Mongolian population and support the need for large scale epidemiological and genetic investigation.
Purpose:Multiple morphological abnormalities of the sperm flagella (MMAF), uncommonly causing primary infertility, are typical features of aberrant spermatozoa flagellum morphologies, which manifest as shortness, absence, bending, coiling, and irregularity of flagella. CFAP44, an important component of flagella assembly, has attracted significant interest due to its critical role in MMAF pathogenesis. Understanding the variants associated with CFAP44 can provide insights into the molecular mechanisms underlying MMAF. Patients and Methods:A comprehensive clinical evaluation was conducted on an infertile Chinese male patient from a nonconsanguineous family with sever asthenozoospermia (no progressive sperm). By performing whole-exome sequencing (WES), a novel variant of CFAP44 was identified. Sanger sequencing was performed to confirm the variant. To better investigate its pathogenicity, In silico variant analyses, minigene splicing assays and RT-PCR in vivo were performed. Results:As a result, a CFAP44 homozygous deep-intronic variant (NM_001164496.1:c.1890+5G>C) was detected in the proband by WES. Sanger sequencing confirmed this variant in this family. Splice site prediction suggested that this variant may be a disease-causing variant. Then, exon 15 skipping was identified through minigene assays and RT-PCR in vivo, resulting in a 111-bp deletion within the mutated sequence, thereby indicating a disruption in the normal splicing of the CFAP44 transcript. Conclusion:This is the first study to detect a homozygous variant (c.1890+5G>C) within the CFAP44 gene causing MMAF in a Chinese family. Our results confirmed the pathogenicity of this deep-intronic variant and expanded the mutational spectrum of the CFAP44 gene. Consequently, this study may help elucidate the effect of CFAP44 on MMAF and provide a theoretical basis for MMAF.
Purpose: To demonstrate the clinical value of integrating next-generation sequencing (NGS) with long-read sequencing (LRS) for resolving complex F8 variants and guiding personalized reproductive strategies in Haemophilia A (HA). Patients and Methods: A patient with a history of three adverse pregnancy outcomes underwent comprehensive preconception genetic evaluation. NGS-based carrier screening initially excluded common single-gene disorders but flagged complex variants in the F8 gene. Subsequent LRS was employed to characterize the specific structural variations. Results: NGS screening excluded 155 single-gene disorders and normal FMR1 repeats. LRS confirmed F8 intron 1 inversion (Inv1) and a duplication variant, while ruling out intron 22 inversion. The patient was identified as an asymptomatic female carrier. Based on this diagnosis, reproductive counseling recommended spouse testing, preimplantation genetic testing for monogenic diseases (PGT-M) combined with aneuploidy screening (PGT-A), and prenatal diagnosis. Conclusion: This case underscores that while NGS is an effective screening tool, its limitations in detecting structural variations necessitate a stepwise diagnostic approach. Integrating LRS was indispensable for resolving complex F8 variants, transforming ambiguous genetic signals into precise diagnoses. This precision serves as the cornerstone for accurate risk assessment and empowers couples with informed reproductive options, exemplifying a "personalized reproductive blueprint".
Background:The keloids scar is a skin scarring pathology with a higher frequency in the black population. Several genetic polymorphisms, including those of transforming growth factor receptors, have been identified as probable susceptibility genes. This study aimed to characterize the polymorphisms of TGF-βRI, TGF-βRII and identify risk factors associated with keloid scars in Burkina Faso. Methods:This was a cross-sectional study that included 141 subjects with keloids and conducted from April 2021 to April 2022. Genomic DNA was extracted using the "PureLinkTM Genomic DNA Mini kit". Genotyping of TGF-βRI rs111854391, rs121918710, and TGF-βRII rs104893807, rs28934568 polymorphisms was performed using real-time PCR. Results were considered statistically significant at p<0.05. Results:The average age of the study population was 34 ± 15 years and O Rhesus positive blood group (O+) was predominant (36.88%). All subjects (100%) were heterozygous (TG) for rs121918710. Medical or surgical history, family history, blood type, and rs28934568 polymorphism were related to the number of sites of keloids on the body. Patients with a medical history (9.8%) were carriers of the mutant allele C for rs28934568. Mossi ethnic had more than 8 times risk of developing a keloid scar (p=0.030; OR=8.66 (95% CI: 1.230-60.902). Conclusion:The presence in all the patients of the mutated allele for the rs 121918710 polymorphism could explain the involvement of this mutation in the occurrence of keloid scars. In addition, ethnicity and blood type were the risk factors associated with keloids.
Background:Non-invasive prenatal testing (NIPT) based on cell-free fetal DNA (cffDNA) is widely used for screening common fetal aneuploidies. Although fetal fraction (FF) increases with gestational age, the feasibility and performance of NIPT in the early first-trimester, particularly before 10 weeks of gestation, remain incompletely defined. Methods:This retrospective cohort study included 9,708 singleton pregnancies undergoing first-trimester NIPT between 9 weeks 0 days and 13 weeks 6 days of gestation, which was determined by ultrasound using crown-rump length (CRL) measurement. Participants were stratified into two groups based on gestational age at testing (< 10 weeks and ≥ 10 weeks). Multivariable linear regression was used to assess factors associated with fetal fraction, and multivariable logistic regression was applied to evaluate predictors of no-call results (non-reportable NIPT outcome primarily attributed to fetal fraction <4%), adjusting for maternal age and body mass index (BMI). Results:Fetal fraction increased significantly with advancing gestational age. After adjustment for maternal age and BMI, testing performed at ≥ 10 weeks was associated with a higher fetal fraction compared with testing at < 10 weeks (β = 1.58; 95% CI, 1.31 to 1.85; p < 0.001). However, gestational age was not independently associated with the risk of a no-call result (adjusted OR 0.88; 95% CI, 0.68 to 1.16; p = 0.40), and no significant difference in no-call rates was observed between the two gestational age groups (3.78% vs. 3.76%). Conclusion:Although fetal fraction increases after 10 weeks of gestation, gestational age is not an independent determinant of no-call results once fetal fraction adequacy is achieved. NIPT performed in the early first-trimester (< 10 weeks of gestation) demonstrates acceptable analytical feasibility and reliable performance, supporting its use for early prenatal screening under appropriate clinical conditions.
Purpose: To compare pregnancy outcomes and management between patients screening positive for five microdeletions (microdeletion screen-positive, MDS+) and patients screening negative (microdeletion screen-negative, MDS-). Patients and Methods: Patients who received a prenatal cell-free DNA (pcfDNA) test that screens for microdeletions 22q11.2, 15q11.2, 1p36, 4p, and 5p and results were linked to de-identified insurance claims. Diagnosis and procedure codes were used to assess outcomes. Logistic and Poisson regression with adjustment for prior high-risk pregnancy and payer type were used to compare pregnancy outcomes and management in those with MDS+ and MDS-results. Results: A total of 119 MDS+ patients and 287,169 MDS-patients were eligible for analysis. During pregnancy, MDS+ patients were more likely than MDS-patients to have polyhydramnios (18.5% in MDS+ vs. 3.4% in MDS-; OR=6.3 [95% CI: 3.8-10.1]; p<0.001) and fetal growth restriction (22.2% in MDS+ vs. 10.4% in MDS-; OR=2.4 [95% CI: 1.5-3.7]; p<0.001). MDS+ patients were more likely to experience pregnancy loss (OR=3.2; 95% CI: 1.3-6.3; p=0.004) or terminate the pregnancy (OR=22.2 [95% CI: 8.6-46.8]; p<0.001). Among patients with a live birth, MDS+ were more likely to have a preterm delivery (25.0% in MDS+ vs. 15.4% in MDS-; OR=1.8 [95% CI: 1.0-3.0]; p=0.04). MDS+ patients had increased pregnancy management, including more invasive diagnostic testing (13.4% in MDS+ vs. 0.5% in MDS-; OR=31.0 [95% CI: 17.5-51.1]; p<0.001) and more frequent echocardiograms (RR=1.5 [95% CI: 1.2, 1.9]; p<0.001) compared to MDS-pregnancies. Conclusion: MDS+ pregnancies had elevated rates of ultrasound abnormalities, pregnancy loss, preterm birth, and pregnancy management as compared to an MDS-control group. These findings support the clinical utility of microdeletion screening in prenatal care.
Primary ciliary dyskinesia (PCD) is a rare, genetically heterogeneous disorder with variable clinical presentation. In cases where traditional diagnostic tools such as transmission electron microscopy (TEM) or nasal nitric oxide (nNO) measurement are inconclusive/unavailable, molecular diagnostics via whole-exome sequencing (WES) may provide essential insights. In this case report, we present two male infants with diverse phenotypes and genotypes. 1st patient was ultimately diagnosed with PCD thanks to WES, while 2nd patient was strongly suggestive of PCD. The 1st patient portrayed in his clinical history symptoms such as perinatal respiratory distress, situs inversus, and recurrent otitis media. He was found to carry a known pathogenic homozygous variant c.461A>C (p.His154Pro), in the CCDC103 gene. The second patient exhibited more complex phenotype, including diaphragmatic hernia, absence of the pericardium, significant delay in the motor development. WES identified two variants in both DNAH5 and DNAH9. Parental testing identified the maternal origin for the c.10243-6C>T (p.?) and c.308del (p.Phe103Serfs*31) variants in the DNAH9 gene and a paternal origin for the c.1206T>A (p.Asn402Lys) variant in the DNAH5 gene. The second variant c.5124G>T (p. Glu1708Asp) in the DNAH5 gene in the proband arose de novo. At the time of analysis, these variants were classified as variants of uncertain significance (VUS) or likely benign, with limited segregation data and no definitive functional validation. Although the genetic findings were not diagnostic on their own, the clinical picture (situs inversus, neonatal respiratory distress, recurrent infections) was strongly suggestive of PCD. Both cases illustrate the crucial role of WES in establishing a molecular diagnosis of PCD, particularly when the use of traditional diagnostic methods is inconclusive. Moreover, they demonstrate the value of genomic testing in guiding the clinical management and informing about prognosis in diseases like PCD.
Mandibulofacial dysostosis with microcephaly (MFDM) is caused by haploinsufficiency of EFTUD2 gene. This syndrome is characterized by microcephaly, malar and mandibular hypoplasia, ear abnormalities, developmental delay, and intellectual disability. In this study, we report two cases of fetuses presenting a phenotype consistent with MFDM and confirmed EFTUD2 gene variants. The patients were referred following abnormal ultrasound findings. Genetic diagnostics in both cases revealed heterozygous variants in the EFTUD2 gene that had not been previously reported prenatally. In the first patient, exome sequencing identified a c.2698_2701del p. (Val865Serfs*34), while in the second a novel large deletion involving multiple genes, including the entire EFTUD2 gene, was detected by microarray analysis. Prenatal diagnosis of MFDM requires precise ultrasound assessment. Therefore, consideration of characteristic features observed in fetuses with MFDM is essential for differential diagnosis and guiding targeted genetic testing.
According to OMIM and Orphanet databases, Schaaf-Yang syndrome (SYS) (OMIM: 615547, ORPHA: 398069) is a rare genetic disorder that shares certain clinical features with Prader-Willi syndrome (PWS), including hypotonia, developmental delay, and early-onset obesity. However, SYS often exhibits a more complex and variable phenotype. Missense variants in MAGEL2 have been reported only rarely, and their phenotypic spectrum appears milder and more variable than that of truncating mutations. Data on early-onset obesity as a dominant feature in such patients are limited. In this case report, we describe a child with mild phenotype (SYS) carrying the novel missense variant MAGEL2(NM_019066.5):c.1265C>T (p.Pro422Leu) presenting with severe early-onset obesity and a comparatively neurodevelopmental phenotype. We present a case of a boy with neonatal hypotonia, diagnosed with (SYS) at age 9 years, with follow-up to age 11 years. The boy was born at 34+3 weeks of gestation with hypotonia, feeding difficulties, and a persistent ductus arteriosus that required surgical ligation in early infancy. In the following years, he developed severe early-onset obesity, already evident by age 2 despite multidisciplinary care. Genetic testing performed at age 9 years identified a novel missense variant (NM_019066.5)c.1265C>T in the MAGEL2 gene, which was not inherited from his mother, thereby confirming the diagnosis of (SYS). At the time of the most recent evaluation, at age 11 years, he remained under long-term follow-up. Clinical management over this period included endocrine therapy, cardiac surgery, physical rehabilitation, and dietary interventions, and despite the complexity of his condition, long-term stabilization of his BMI percentile was achieved with consistent non-pharmacological interventions. This case highlights the importance of early multidisciplinary investigation and intervention in SYS, particularly when obesity is the dominant feature. Effective long-term weight stabilization is possible through structured lifestyle management.
Purpose:The aim of the study was to evaluate hearing, voice, and speech in 10-year-old boy with fascio-scapulo-humeral dystrophy (FSHD). Patients and Methods:Hearing, voice, and speech were assessed in a 10-year-old boy with FSHD due to scarcity of detailed audiophonological assessment in this disorder. Evaluation of muscle tension in upper and lower limb posture, gait, muscle enzyme activity, ECG, USG, bone densitometry, lower limb muscles MRI, handgrip strength were conducted. Hearing was examined using pure-tone, impedance, speech audiometry, and DPOAE. Voice assessment included GRBAS and endoscopic laryngeal examinations. Speech evaluation was conducted using Child Speech Assessment Cards (Karty Oceny Logopedycznej Dziecka, KOLD). Results:Diagnosis of FSHD was genetically confirmed by haplotype testing. Muscle hypotonia and atrophy were observed in limbs and face, along with gait disturbances. The 6-minute walk test (6MWT) result was 570 m, and the upper limb muscle strength was 9.3 kg (right limb) and 11.0 kg (left limb), both limbs: 15.7 kg. Audiological evaluation revealed severe bilateral sensorineural hearing (mean 73 dB HL). Bilateral type As tympanogram was recorded (right ear: 0.27 mL; left ear: 0.18 mL). Stapedial reflex was absent at high frequencies. DPOAE testing revealed sporadic bilateral cochlear responses. Speech audiometry showed reduced speech comprehension. Endoscopic examinations revealed edema of both vocal folds mucosa, preserved mobility. GRBAS scale showed G2R1B3A3S0. Acoustic analysis demonstrated slight reduction in fundamental frequency (F0) and elevated shimmer (10.566%). MPT was slightly shortened to 20 s. Speech evaluation revealed mouth breathing, shortened expiratory phase during phonation, bradylalia, articulation disorders with prolonged pauses between words, high-arched soft palate, shortened lingual frenulum, open bite, reduced tone of facial, lip, and tongue muscles. Conclusion:Genetic testing confirmed the presence of facio-scapulo-humeral muscular dystrophy (FSHD). Bilateral severe sensorineural hearing loss was documented. Speech disorders in FSHD were associated with reduced tension of articulatory muscles.
A solitary plexiform neurofibroma in a 15-year-old girl prompted an unexpected referral for neurofibromatosis type 1 (NF1) evaluation. Initially excised under the impression of a lipoma, the lesion's histopathology revealed neural origin features with strong S100 and CD34 positivity. Dermatologic examination uncovered multiple café-au-lait macules, and subsequent referral to neurology raised clinical suspicion for NF1. This case emphasizes how incidental histological findings in a benign-appearing lesion can serve as the first clinical clue of a genetic disorder, triggering appropriate multidisciplinary evaluation.
Background:Chronic obstructive pulmonary disease (COPD) poses a significant health burden in Vietnam. The TNF-α rs1800629 (-308G/A) polymorphism is an influential factor in disease pathogenesis. However, its association is inconsistent across the studied populations. This study addresses this gap in Vietnam by examining allele frequencies and clinical associations in stable COPD patients. Methods:A cross-sectional study recruited 320 healthy controls and 266 stable COPD patients (per GOLD 2023 criteria) from October 2024 to August 2025. Clinical data were collected from medical records and direct interrogation. Genotyping was performed using PCR-RFLP. The dataset used for sensitivity analyses (2,660 observations) was created through multiple imputations to address missing clinical data. Associations of the rs1800629 with disease susceptibility and selected clinical management parameters were analyzed using Chi-square/Fisher's exact tests, multivariable logistic regression, and sensitivity analysis. Results:The A allele frequencies were 8.83% (COPD), 6.88% (controls), and 7.77% overall (p > 0.05). Patients were predominantly male smokers over 40 years, with moderate-severe symptoms (CAT ≥10, mMRC 3) and A/B severity groups. Under a recessive model, the AA genotype was associated with ~96% reduced susceptibility (adjusted OR 0.039, 95% CI 0.002-0.62, p=0.022). Regression identified smoking (OR 1.83-2.35), family history (OR 2.04), and onset ≥40 years (OR 2.88-3.36) as independent symptom influences. Sensitivity analysis further supported the protective effect of the AA genotype and revealed GA protective effects on symptomatic outcomes (OR<1, p<0.05). Conclusion:Our findings suggest a possible protective recessive association of the TNF-α rs1800629 (-308G/A) polymorphism with COPD susceptibility, symptom burden, and exacerbation risk. However, the wide confidence intervals arising from the rarity of the AA genotype and the use of multiply imputed data mean these signals are exploratory. Larger multi‑center studies with comprehensive exposure assessment are needed to confirm these observations.
Familial partial lipodystrophy type 2 (FPLD2), or Dunnigan syndrome, is a rare autosomal dominant disorder caused by mutations in the lamin A (LMNA) gene, most frequently involving the p.R482W variant. It is characterized by regional loss of subcutaneous fat and severe metabolic abnormalities, particularly dyslipidemia, insulin resistance, and hepatic steatosis. We report a family with three individuals -mother and two siblings- carrying the same pathogenic LMNA c.1444C>T (p.R482W) variant but exhibiting distinct clinical and biochemical profiles. The proband (patient 1) is a 29-year-old male, presented with moderate metabolic disturbances, including hypertriglyceridemia, low levels of high density lipoprotein-cholesterol (HDL-C), and hepatic steatosis, accompanied by physical features such as dorsocervical fat accumulation and winged neck. His dizygotic female twin (patient 2) exhibited a more severe phenotype with triglycerides levels approached 700 mg/dL, insulin resistance, and polycystic ovarian morphology (PCOM). Their 68-year-old mother, also a carrier, showed only mild dyslipidemia and unstable angina. The comparison of dizygotic twins and their mother carrying the same LMNA variant provides a unique opportunity to illustrate how sex, age, and hormonal status modulate metabolic severity in FPLD2. These findings reinforce the clinical relevance of family-based evaluation and early metabolic surveillance, even in mildly affected or asymptomatic carriers.
Objective: Retinitis pigmentosa (RP) is a genetically heterogeneous group of inherited retinal dystrophies often accompanied by macular involvement. Variants in IMPG2 are known to cause RP type 56 and vitelliform macular dystrophy type 5, but the pathogenic role of deep intronic variants has rarely been characterized. This study aimed to identify and functionally validate a novel deep intronic IMPG2 variant in a patient with RP. Methods: A comprehensive clinical, genetic, and functional assessment was performed. Ophthalmic evaluations included fundus photography, optical coherence tomography (OCT), OCT angiography (OCTA), and multifocal electroretinography (mfERG). Wholegenome sequencing followed by Sanger validation and segregation analysis was conducted. In silico splicing prediction and dual minigene assays (pcMINI and pcMINI-C) in HEK293T and HeLa cells were employed to evaluate the splicing effect of the variant. Results: A novel homozygous deep intronic variant in IMPG2 (NM_016247.4:c.909-1659A>G), absent from public databases, was identified. Splice prediction tools suggested creation of a cryptic donor site. Functional assays demonstrated aberrant splicing with retention of a 132 bp pseudoexon, introducing a premature termination codon and thereby likely triggering nonsense-mediated decay rather than generating a stable truncated protein. Segregation analysis confirmed autosomal recessive inheritance. The proband exhibited lifelong night blindness, progressive peripheral visual field constriction, and macular structural and functional impairment, consistent with IMPG2-associated retinopathy. Conclusion: This study provides the first functional evidence that a deep intronic IMPG2 variant causes pseudoexon activation leading to a premature termination codon and likely nonsense-mediated decay. These findings expand the IMPG2 mutational spectrum, highlight the pathogenic potential of deep intronic variants, and emphasize the importance of functional assays for reclassifying variants of uncertain significance in inherited retinal diseases.
Purpose:Despite the rapid expansion of noninvasive genomic technologies, invasive procedures such as chorionic villus sampling (CVS) remain indispensable for providing definitive, early prenatal genetic diagnoses. This study aimed to assess the diagnostic value and effectiveness of CVS in the early detection of chromosomal and genetic abnormalities in a cohort of 912 Polish women. Patients and Methods:This retrospective cohort study included 912 CVS procedures performed between 2010 and 2024 at a tertiary referral center. Indications, sampling success rates, and genetic results were analyzed. Fetal samples were examined using conventional karyotyping, chromosomal microarray analysis, and digital PCR. Results:Of 912 procedures, 903 (99.0%) were technically successful, with 844 included in the final cytogenetic analysis. The most common indication was abnormal ultrasound findings (79.9%). Chromosomal abnormalities were found in 40.05% of cases, with trisomy 21 (16.8%), trisomy 18 (8.8%), trisomy 13 (3.1%) and monosomy X (4.6%) being the most frequent. Mosaicism was detected in 8 cases, and maternal cell contamination in 9. Conclusion:CVS is a valuable method of early prenatal genetic diagnosis, especially in high-risk pregnancies, where early and personalized genomic assessment can have a significant impact on clinical decision-making. Emerging genomic technologies are likely to complement CVS, underscoring its continued relevance in genomic medicine and personalized prenatal care.
Mutations in the SACS gene are associated with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), a clinically and genetically heterogeneous neurodegenerative disorder. ARSACS typically manifests as slowly progressive ataxia with spasticity and sensorimotor neuropathy. Nevertheless, an array of additional features may also be observed, including hearing impairment, epileptic seizures, and even the absence of spasticity. Reports of SACS mutations in Polish patients are rare. Here we report a compound heterozygous pathogenic variants in the SACS gene, a novel duplication of exon 6, and a frameshift deletion c.12923_12927del 12921_12925del p.(Lys4308SerfsTer21) in a Polish patient presenting with progressive ataxia, spasticity, and peripheral neuropathy. This is the first case with a rearrangement of a complete single exon of the SACS gene. We also review six previously described Polish individuals with SACS variants, noting that all presented with cerebellar ataxic gait and cerebellar atrophy on brain MRI scans. Across these cases, nine rare pathogenic SACS variants were identified. This study adds to the ARSACS-associated mutation spectrum, provides further insights into genotype-phenotype correlations, and highlights the importance of testing for structural variants.
Objective:To analyze the incidence of different types of Y chromosome microdeletions in infertile male patients in China, and to investigate the relationship between microdeletions in different azoospermia factor (AZF) regions and sperm kinetic parameters, sperm morphological parameters, and sex hormone levels. Methods:A total of 2010 infertile male patients who visited the Fujian Provincial Maternity and Child Health Hospital from 2022 to 2025 were selected. Their Y chromosome microdeletions (YCMD), semen routine, sperm morphology, sperm DNA fragmentation index (DFI), and sex hormone levels were detected, and the relationships between these parameters were analyzed. Results:The incidence of Y chromosome microdeletions in patients was 8.66% (174/2010). Among the 174 patients with AZF microdeletions, the proportion of AZFc region deletions was 85.63% (149/174), AZFa region deletions accounted for 2.30% (4/174), AZFb/c region deletions accounted for 8.05% (14/174), AZFa/b/c region deletions accounted for 2.87% (5/174), and heterochromosome deletions accounted for 1.15% (2/174). There were no statistically significant differences in semen volume, testosterone (T), and prolactin (PRL) levels between patients with different types of AZF deletions and the normal group (P>0.05). There were statistically significant differences in sperm concentration, progressive motility (PR), non-progressive motility (NP), total sperm motility, normal sperm morphology rate, sperm DFI, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) between patients with different types of AZF deletions and the normal group (P<0.05). Conclusion:AZFc deletion is the most common type of Y chromosome microdeletion in infertile male patients in China. Patients with AZFa and AZFa/b/c combined deletions often present with azoospermia. AZFc deletion is associated with abnormal sperm quality parameters and disordered hormone levels.
Background:Partial monosomy of chromosome 21q is a rare genetic disorder characterized by a wide spectrum of clinical manifestations including intellectual disability, developmental delay, and distinctive craniofacial features. Concurrent deletions involving chromosome 15q26 are also infrequent and typically benign. Objective:This study reports a rare case of de novo unbalanced translocation between chromosomes 15q26.3 and 21q22.11, resulting in partial monosomy 21q and a benign deletion of 15q26.3, highlighting the importance of comprehensive cytogenetic and molecular analysis. Methods:Peripheral blood samples from the proband and her parents were analyzed using GTG-banding karyotype, fluorescence in situ hybridization (FISH), and whole-genome oligo-array comparative genomic hybridization (array CGH). Results:The proband, a 36-year-old woman with intellectual disability and developmental delay, exhibited a karyotype of 45,XX,der(15)t(15;21)(q26.3;q22.11),-21. Array CGH revealed a 17.32 Mb deletion at 21q11.2q22.11 encompassing 37 genes, and a benign 673 kb deletion at 15q26.3 involving 13 genes. Clinical features included multiple craniofacial dysmorphisms, low birth weight, short stature, and dental anomalies. Conclusion:This case represents the first reported instance from Iran of a pathogenic partial monosomy 21q due to an unbalanced translocation with chromosome 15q26.3. The findings underscore the critical role of integrated cytogenetic and molecular diagnostics in identifying complex chromosomal rearrangements and contribute to the understanding of genotype-phenotype correlations in partial monosomy 21q.
