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• Distyly is an intriguing floral adaptation that increases pollen transfer precision and restricts inbreeding. It has been a model system in evolutionary biology since Darwin. Although the S-locus determines the long- and short-styled morphs, the genes were unknown in Turnera. We have now identified these genes. • We used deletion mapping to identify, and then sequence, BAC clones and genome scaffolds to construct S/s haplotypes. We investigated candidate gene expression, hemizygosity, and used mutants, to explore gene function. • The s-haplotype possessed 21 genes collinear with a region of chromosome 7 of grape. The S-haplotype possessed three additional genes and two inversions. TsSPH1 was expressed in filaments and anthers, TsYUC6 in anthers and TsBAHD in pistils. Long-homostyle mutants did not possess TsBAHD and a short-homostyle mutant did not express TsSPH1. • Three hemizygous genes appear to determine S-morph characteristics in T. subulata. Hemizygosity is common to all distylous species investigated, yet the genes differ. The pistil candidate gene, TsBAHD, differs from that of Primula, but both may inactivate brassinosteroids causing short styles. TsYUC6 is involved in auxin synthesis and likely determines pollen characteristics. TsSPH1 is likely involved in filament elongation. We propose an incompatibility mechanism involving TsYUC6 and TsBAHD.

Congenital arginine vasopressin resistance (AVP-R) is a rare inherited disorder caused by renal unresponsiveness to arginine vasopressin (AVP), leading to persistent polyuria and polydipsia. We report a 19-year-old male individual with a long history of excessive thirst and urination who remained undiagnosed until adulthood. Despite normal growth and development, he was found to have bilateral hydronephrosis and underwent pyeloplasty at age 19. Postoperative fluid restriction resulted in life-threatening hypernatremia and seizures. Further evaluation revealed persistently low urine osmolality despite hypernatremia, elevated plasma copeptin, and no response to desmopressin or vasopressin, confirming AVP-R. Genetic testing identified a hemizygous arginine vasopressin receptor 2 (AVPR2) missense variant (c.357G>C; p.Gln119His), confirming X-linked congenital AVP-R. Treatment with thiazide diuretic, sodium restriction, and liberal fluid intake led to symptom relief and biochemical stability. This case highlights the diagnostic challenges of congenital AVP-R in patients without growth impairment and underscores the importance of molecular confirmation for appropriate management and family screening.

Isocitrate dehydrogenase (IDH)-mutant astrocytoma with microvascular proliferation, necrosis, CDKN2A/B homozygous deletion, or any combination of these features corresponds to World Health Organization grade 4 according to current criteria. However, the prognostic significance of CDKN2A hemizygous deletion in IDH-mutant astrocytoma is not well established. We undertook a comprehensive study that included assessments of histological and genetic approaches to prognosis for these tumors. Samples from a cohort of 114 patients with extended observation were subjected to histological review and molecular analysis. CDKN2A (9p21) deletion was detected by fluorescence in situ hybridization. Overall survival (OS) was calculated via Kaplan-Meier estimation using the log-rank test. Histological grade, Ki-67 index, and the extent of surgical resection correlated with the OS of IDH-mutant astrocytoma patients. Both CDKN2A homozygous deletion and hemizygous deletion were detectable. Patients with CDKN2A homozygous-deletion tumors had the poorest OS; those with CDKN2A hemizygous-deletion tumors had an intermediate OS (p < .001). We then established a novel grading system that combined CDKN2A homozygous and hemizygous deletions with histological grade; the combined grading system was an independent prognostic factor for IDH-mutant astrocytomas. We conclude that CDKN2A homozygous and hemizygous deletion should be combined in a grading system for IDH-mutant astrocytomas.

Background: Fragile XE (FRAXE) is an X-linked recessive condition that affects 1 in 50,000 of new born males with intellectual disability (ID). It is characterized by mild Intellectual disability (ID), speech delay cognitive impairment, and in some cases with phenotypes of Autism Spectrum disorder (ASD). Methodology: In this study, a family was investigated with two male siblings having neuro developmental delay. Whole exome sequencing analysis (WES) was carried out to identify the pathogenic variant. Sanger sequencing was performed in normal and affected family members and co-segregation analysis was done. Results: Two probands were affected in a family diagnosed with intellectual disability. A novel hemizygous variant (c.3348G>T, p.Asp1150Tyr) in AFF2 gene was identified as the causal variant cause in affected individuals. This variant was novel from Pakistani population. Conclusion: In this study, a novel hemizygous variant (c.3348G>T, p.Asp1150Tyr) identified in AFF2. These findings paved the way for further studies on genetic and clinical spectrum of rare X-linked recessive disease involved in ID.  

Abstract Hybridization and genome duplication have played crucial roles in the evolution of many animal and plant taxa. The subgenomes of parental species undergo considerable changes in hybrids and polyploids, which often selectively eliminate segments of one subgenome. However, the mechanisms underlying these changes are not well understood, particularly when the hybridization is linked with asexual reproduction that opens up unexpected evolutionary pathways. To elucidate this problem, we compared published cytogenetic and RNAseq data with exome sequences of asexual diploid and polyploid hybrids between three fish species; Cobitis elongatoides, C. taenia, and C. tanaitica. Clonal genomes remained generally static at chromosome-scale levels but their heterozygosity gradually deteriorated at the level of individual genes owing to allelic deletions and conversions. Interestingly, the impact of both processes varies among animals and genomic regions depending on ploidy level and the properties of affected genes. Namely, polyploids were more tolerant to deletions than diploid asexuals where conversions prevailed, and genomic restructuring events accumulated preferentially in genes characterized by high transcription levels and GC-content, strong purifying selection and specific functions like interacting with intracellular membranes. Although hybrids were phenotypically more similar to C. taenia, we found that they preferentially retained C. elongatoides alleles. This demonstrates that favored subgenome is not necessarily the transcriptionally dominant one. This study demonstrated that subgenomes in asexual hybrids and polyploids evolve under a complex interplay of selection and several molecular mechanisms whose efficiency depends on the organism’s ploidy level, as well as functional properties and parental ancestry of the genomic region.

Charcot-Marie-Tooth disease (CMT) is a genetically heterogeneous disorder. As more genes are identified and overlapping of neuropathy phenotypes, the traditional classification of CMT often proves inadequate. A young male with typical clinical features was suspected to have CMT, but family history about the inheritance pattern and distinct features suggestive of particular subtypes were lacking. He was directly evaluated by whole exome sequencing (WES). The libraries from extracted DNA were sequenced on Illumina sequencing platform. The variant detected in WES was confirmed by Sanger sequencing. WES shows a likely pathogenic hemizygous missense variation in exon 2 of the gap junction protein beta 1(GJB1) gene (chrX: 70444104; C > T; Depth: 66x) that results in the substitution of cysteine for arginine at codon 183 (p.Arg183Cys). This novel variation expands the spectrum of GJB1 mutations associated with X-linked CMT (CMTX) to establish a specific genetic cause.

The current study aimed to explore phenotypic evolution in Fabry disease according to demographics, genotype, specific enzyme activity and pathogenicity scores. We integrated clinical, biochemical, and genomic data of 88 Fabry cases (23 from our cohort, 65 from other published data on Indians) to achieve this objective. The affected cases showed profound impairment in the alpha galactosidase enzyme activity (0.73 ± 1.38% mean normal) while carriers showed 15.64 ± 3.68% mean normal activity. The mutation spectrum is highly heterogeneous with eight different mutations identified in eight different patients in our cohort, while the total data is representative of 68 mutations in Indians. The mean CADD score for these mutations was 20.63 ± 10.38. Highly conserved mutations are associated with renal involvement ( p  = 0.005), while neuropathic pain is observed even in mutations in less conserved regions ( p  = 0.02). The age of onset showed a positive association with the percentage of specific enzyme activity ( r  = 0.375, p  < 0.001), renal disease ( r  = 0.328, p  = 0.005), and cardiac problems ( r  = 0.278, p  = 0.026). Consistent with this, we had a very early onset neonatal Fabry with 0% specific enzyme activity harbouring c.613C > G (p.Pro205Ala) mutation in the GLA gene. This emphasizes that many patients with rare genetic diseases can experience delays in diagnosis due to their infrequent occurrence and nonspecific symptoms, which are not easily recognizable. A holistic approach with a combination of WES and biochemical assays will be helpful in arriving at the early and accurate diagnosis through rigorous phenotypic evaluation.

Purpose To report a novel hemizygous nonsense variant in the CACNA1F gene associated with congenital stationary night blindness (CSNB) in a pediatric patient, emphasizing the utility of portable electroretinography (ERG) and genetic testing in diagnosing unexplained visual impairments. Methods The patient, a 5-year-old male, underwent comprehensive clinical evaluation, including detailed anterior segment and fundus examinations, full-field electroretinogram (ffERG) using a RETeval™ portable device, and whole exome sequencing (WES) to elucidate the genetic basis of his visual impairment. Structural modeling of the mutated protein was performed using SWISS-MODEL and PYMOL. Results Best-corrected visual acuity was 0.4 logMAR bilaterally, with unremarkable anterior segment and fundus examinations. FFERG revealed significant abnormalities consistent with incomplete CSNB: severely reduced rod response in dark-adapted (DA) 0.01, negative waveform with b/a wave ratio < 1.0 in DA 3.0, and diminished cone response in light-adapted ERG. WES identified a novel pathogenic variant in the CACNA1F gene (c.1234G > T, p.E412*), inherited maternally. This variant introduces a premature stop codon at position 412, likely resulting in a truncated CACNA1F protein. Conclusions This case highlights the importance of comprehensive clinical assessments and genetic testing in pediatric patients with unexplained visual impairments, revealing a novel CACNA1F variant that expands our understanding of CSNB. The use of a portable ERG device proved particularly valuable in assessing retinal function in this young patient. Further investigations are warranted to elucidate the clinical implications of this novel pathogenic variant.

Background: Fragile XE (FRAXE) is an X-linked recessive condition that affects 1 in 50,000 of new born males with intellectual disability (ID). It is characterized by mild Intellectual disability (ID), speech delay cognitive impairment, and in some cases with phenotypes of Autism Spectrum disorder (ASD). Methodology: In this study, a family was investigated with two male siblings having neuro developmental delay. Whole exome sequencing analysis (WES) was carried out to identify the pathogenic variant. Sanger sequencing was performed in normal and affected family members and co-segregation analysis was done. Results: Two probands were affected in a family diagnosed with intellectual disability. A novel hemizygous variant (c.3348G>T, p.Asp1150Tyr) in AFF2 gene was identified as the causal variant cause in affected individuals. This variant was novel from Pakistani population. Conclusion: In this study, a novel hemizygous variant (c.3348G>T, p.Asp1150Tyr) identified in AFF2. These findings paved the way for further studies on genetic and clinical spectrum of rare X-linked recessive disease involved in ID.  

X-linked recessive ichthyosis (XLI) is clinically characterized by dark brown, widespread dryness with polygonal scales. We describe the identification of STS and PUDP deletions using targeted panel sequencing combined with copy-number variation (CNV) analysis in XLI. A 9-month-old infant was admitted for genetic counseling. Since the second day after birth, the infant’s skin tended to be dry and polygonal scales had accumulated over the abdomen and upper extremities. The infant’s maternal uncle and brother (who had also exhibited similar skin symptoms from birth) presented with polygonal scales on their trunks. CNV analysis revealed a hemizygous deletion spanning 719.3 Kb on chromosome Xp22 (chrX:7,108,996–7,828,312), which included a segment of the STS gene and exhibited a Z ratio of −2 in the proband. Multiplex ligation-dependent probe amplification (MLPA) confirmed this interstitial Xp22.31 deletion. Our report underscores the importance of implementing CNV screening techniques, including sequencing data analysis and gene dosage assays such as MLPA, to detect substantial deletions that encompass the STS gene region of Xq22 in individuals suspected of having XLI.