Autosomal Recessive Inheritance Research Articles

A pathogenic COL7A1 variant highlights semi-dominant inheritance in dystrophic epidermolysis bullosa

Dystrophic epidermolysis bullosa is a rare subtype of inherited epidermolysis bullosa, caused by variants in the collagen type VII alpha 1 chain (COL7A1) gene (MIM120120). Both autosomal dominant and recessive inheritance has been reported with variable phenotype. We investigated a Pakistani family with dystrophic epidermolysis bullosa via exome sequencing and identified a pathogenic nonsense variant in COL7A1 NM_000094 c.1573 C > T:p.(Arg525*). The inheritance pattern observed was consistent with a semi-dominant model, where heterozygous parents exhibited a mild phenotype, and homozygous children were more severely affected. For dystrophic epidermolysis bullosa, loss-of-function variants are typically associated with the autosomal recessive form, while missense variants are linked to the autosomal dominant form. A review of the literature suggests a semi-dominance pattern for some missense variants, particularly glycine substitutions, but this concept had not been formally recognized. This study highlights the importance of considering semi-dominant inheritance models for dystrophic epidermolysis bullosa and other Mendelian diseases with an autosomal recessive mode of inheritance, as it can significantly impact diagnosis and genetic counseling.

Heterozygous pathogenic STT3A variation leads to dominant congenital glycosylation disorders and functional validation in zebrafish

BackgroundCongenital disorders of glycosylation are a rare group of disorders characterized by impaired glycosylation, wherein STT3A encodes the catalytic subunit of the oligosaccharyltransferase complex, which is crucial for protein N-glycosylation. Previous studies have reported that STT3A-CDG is caused by autosomal recessive inheritance. However, in this study, we propose that STT3A-CDG can be pathogenic through autosomal dominant inheritance.MethodsThe variant was identified via trio whole-exome sequencing. We constructed wild-type and variant plasmids, transfected them into HEK293T cells and detected the expression levels of the STT3A protein. We performed CRISPR-Cas9 to establish heterozygous knockdown zebrafish to validate the functional implications of autosomal dominant inheritance of STT3A in pathogenesis.ResultsThe patient presented with developmental delay, distinctive facial features, short stature, and abnormal discharges. The heterozygous pathogenic missense variant (NM_001278503.2: c.499G > T, NP_001265432.1:p. Asp167Tyr) was identified, and the Western blot results revealed a significant decrease in protein levels. Heterozygous knockdown zebrafish exhibit phenotypes similar to those of patients, including craniofacial dysmorphology (increased eye distance, increased Basihyal’s length, increased Ceratohyal’s angle), skeletal abnormalities (reduced number of mineralized bones), developmental delay (reduced adaptability under light‒dark stimuli suggesting abnormal locomotion, orientation, and social behavior), and electrophysiological abnormalities.ConclusionWe report a proband with a dominant congenital glycosylation disorder caused by heterozygous pathogenic STT3A variation, which is a new inheritance pattern of STT3A. Our report expands the known phenotype of dominant STT3A-CDGs. Furthermore, we provide in vivo validation through the establishment of a heterozygous knockdown zebrafish model for stt3a and strengthened the compelling evidence for dominant STT3A-related pathogenesis.

P-05 17Β-HYDROXYSTEROID DEHYDROGENASE 3 DEFICIENCY: TWO CASE REPORTS

Abstract Introduction 17-β-hydroxysteroid dehydrogenase type3 (17β-HSD3) is an enzyme that produces testosterone from androstenedione, encoded by the HSD17B3 gene. Its deficiency causes 46 XY disorder of sex development (DSD) with autosomal recessive inheritance. 46 XY individuals with this enzyme deficiency can exhibit a wide range of phenotypes, ranging from normal female external genitalia to ambiguous genitalia. In early childhood, the diagnosis might be clinically indistinguishable from other causes of 46 XY DSD such as partial androgen insensitivity syndrome (AIS) and 5α-reductase type 2 deficiency. Laboratory diagnosis is based on a low testosterone/androstenedione ratio. The diagnosis is confirmed by molecular genetic testing. If the diagnosis is missed in early infancy, patients present with severe virilization symptoms and amenorrhea during puberty. We present two siblings followed and managed with a presumed diagnosis of AIS until the genetic testing was performed. Clinical Case 1 A 4-month-old patient with female external genitalia was operated on with suspicion of bilateral inguinal hernia, and pathologic investigation revealed immature testicular tissue. No uterus and ovaries could be detected by pelvic ultrasound. The karyotype analysis was consistent with 46 XY, and the patient was followed up with the diagnosis of AIS. The patient’s parents were first cousins. The patient was started on estradiol replacement when she was 13 years old. At the age of 21, she underwent vaginoplasty due to a 2 cm long vaginal canal. A genetic analysis was available when the patient was 21 years old. Next generation sequencing revealed a previously reported homozygous c.277+5g>A mutation in exon 3 of HSD17B3 gene. The diagnosis was established as 17β-HSD3 deficiency. Clinical Case 2 After the index case was diagnosed with AIS karyotype analyses were performed on three other siblings at the time. The patient’s 7 years old sibling, who had a complete female-appearing genitalia, had a karyotype of 46XY. As the presumed diagnosis was AIS, bilateral orchiectomy was performed after counselling. Estradiol replacement was started at the age of 14 and complete breast development was achieved. Vaginal length was reported as 8 cm. Further genetic analysis was performed at the age of 27 and it revealed that the two siblings shared the same genetic mutation. Both preferred to retain the female gender identity during adulthood. Two other female siblings with a karyotype of 46XX and both parents had a heterozygous c.277+5g>A mutation in the HSD17B3 gene. Conclusion Although clinical evaluation and laboratory test results might point out to 17-β-HSD3 deficiency, the definite diagnosis is established with genetic testing. As these patients might develop male gender identity, awareness of the disease and early genetic testing is of importance for the prevention of misdiagnoses, counselling for gender identity, deciding on surgical interventions, and management of these patients.

Revealing Molecular Diagnosis With Whole Exome Sequencing in Patients With Inherited Retinal Disorders.

Inherited retinal diseases (IRDs) constitute a heterogeneous group of clinically and genetically diverse conditions, standing as a primary cause of visual impairment among individuals aged 15-45, with an estimated incidence of 1:2000. Our study aimed to comprehensively evaluate the genetic variants underlying IRDs in the Turkish population. This study included 50 unrelated Turkish IRD patients and their families. Genomic DNA was extracted from each participant, and candidate variants were identified via next-generation sequencing to determine their pathogenicity. We detected variants in 58% of the patients, of which six novel variants were identified. Among these, 16 cases exhibited variants associated with retinitis pigmentosa and Stargardt disease, while 13 presented variants linked to other retinal diseases. The spectrum of identified variants included 21 homozygous cases and five compound heterozygous variants, both indicative of autosomal recessive inheritance. Three cases revealed heterozygous variants suggestive of autosomal dominant inheritance, and two cases featured hemizygous variants suggestive of X-linked inheritance. Importantly, no matches with copy number variants were detected in our analysis. This study comprehensively portrays clinical and genetic profiles within the Turkish population affected by IRDs. Identifying novel variants and delineating inheritance patterns contribute to a deeper understanding of the genetic diagnosis of IRDs, paving the way for more precise diagnostic and therapeutic interventions.

Prenatal phenotype of PNKP-related microcephaly, seizures, and developmental delay: A case report and literature review.

Microcephaly, epilepsy, and developmental delay (MCSZ) is a rare neurodevelopmental disorder associated with autosomal recessive inheritance of mutations in the polynucleotide kinase 3'-phosphatase (PNKP) gene. Prompt identification and management are essential, as delayed diagnosis or intervention may result in severe complications or mortality. In this case, prenatal screening in the second trimester detected fetal microcephaly with a gradual decline in head circumference, prompting the decision to terminate the pregnancy. Subsequent genetic analysis of the fetal tissue confirmed the presence of compound heterozygous mutations in the PNKP gene. The patient, a 34-year-old remarried female with no history of consanguineous marriage, underwent 2 mid-trimester termination procedures due to fetal microcephaly and sought counseling for reproductive assistance. The patient's carrier status for PNKP mutations was ascertained through whole-exome sequencing of the termination tissue and molecular genetic testing for monogenic disorders. The terminated fetus was diagnosed with MCSZ, a condition associated with compound heterozygous mutations in the PNKP gene. Fetal microcephaly was identified via mid-trimester prenatal ultrasound, leading to the termination of the pregnancy during the same trimester. Subsequent genetic analysis of the immediate family revealed compound heterozygous mutations in the PNKP gene as the underlying cause of MCSZ. Genetic counseling was provided, followed by 1 cycle of preimplantation genetic testing for monogenic. The patient carried the heterozygous c.1188 + 1G > A PNKP mutation, whereas her husband carried the heterozygous c.976G > A PNKP mutation. The fetus was found to have compound heterozygous mutations c.976G > A and c.1188 + 1G > A. After counseling, the couple underwent 1 cycle of preimplantation genetic testing for monogenic, unfortunately, no pregnancy occurred after the 2 embryos were transferred. MCSZ, a condition caused by PNKP mutations, is exceedingly rare. Women with a history of adverse pregnancy outcomes should undergo close monitoring during prenatal checkups. If fetal microcephaly is detected, it is essential to strictly follow obstetric guidelines for prenatal care, such as comprehensive cranial magnetic resonance imaging and genetic testing for confirmation. Avoidance of consanguineous marriages is advised. Early detection and timely intervention are key to preventing adverse pregnancy outcomes.

Behavioral and Electrophysiological Assessment of Central Auditory Processing in Individuals with Sickle Cell Disease.

Sickle cell anemia has a genetic origin characterized by an autosomal recessive inheritance pattern. The nervous system may be subject to vaso-occlusion and, consequently, affect the proper functioning of the central portion of hearing. To assess central auditory skills and analyze short- and long-latency auditory evoked potentials in children with sickle cell disease. Cross-sectional study. All children had normal hearing thresholds, and their central auditory processing underwent behavioral assessment with a battery of tests involving dichotic and monotic listening, binaural interaction, and temporal processing. The electrophysiological assessment used short- and long-latency auditory evoked potentials. Descriptive statistics were performed. Of the 28 subjects evaluated (mean age of 9.46years), 18 were females and 10 were males. Central auditory processing disorder was identified in 85.7% of the children. The auditory skills of figure-ground for verbal sounds, binaural interaction, and complex temporal ordering were the most affected. An increase in the absolute latencies of Waves III and V was observed in the short-latency potential. Individuals with sickle cell disease have central auditory processing disorder, identified primarily by behavioral assessment.

Deciphering the Genetic and Epidemiological Landscape of Inherited Retinal Diseases (IRDs) in a Cohort of Eastern Iranian Patients.

Inherited retinal diseases (IRDs) may have significant diagnostic challenges due to their genetic complexity and diverse inheritance patterns. Advanced genotyping tools like exome sequencing (ES) offer promising opportunities for identifying causative variants and improving disease management. This retrospective study was aimed to present prevalent pathogenic and novel variants in patients diagnosed with IRDs using ES. We investigated 154 patients diagnosed clinically with IRDs, of which non-syndromic IRDs were more prevalent than syndromic form (~56% vs. ~44%). Out of 154 unrelated patients, 133 (~86%) were genetically resolved, where retinitis pigmentosa was the most common subtype (26% of all resolved patients). Fifty-three previously known and also 56 novel variants across known IRD genes were identified. Autosomal recessive inheritance predominated in both resolved forms (112/133, 84.21%), with 46 novel variants. This could be due to high rate of consanguinity in the studied families (114/133 patients, 85.71%). The two previously reported ancestral founder pathogenic variants in TMEM67 (c.725A > G) and BBS2 (c.471G > A) genes, as well as the most common variant in AIPL1 gene (c.834G > A), were also prevalent in our patients. Interestingly, identical novel compound heterozygote of the CEP290 gene (c.3167C > A and c.7024C > T) were identified in two unrelated cases. This retrospective study was the first attempt in terms of sample size and diversity to add more to our current knowledge of the genetic makeup of IRDs in a population from the East of Iran. Our findings can facilitate genetic counselling and subtype classification of IRDs, especially in challenging cases.

A Case of Late Presenting Retinitis Pigmentosa in an Adult Female

This study aimed to bring to light a case of non-syndromic Retinitis Pigmentosa in a middle-aged female. A 39-year-old female complained of blurred vision that started 3 years ago. It initially affected her distant vision, mainly in low-light conditions, followed by the involvement of near vision as well. On fundus examination, bony spicule-like pigmentation was found peripherally, waxy pallor of the optic disc was present, severe arteriolar attenuation was found, and macular edema was present. The patient was prescribed vitamin A 15,000 IU and asked to come for a follow-up for a low visual aid assessment. This case report highlights the devastating effects of Retinitis Pigmentosa and the need for early diagnosis to slow the progression of vision loss. The peculiarity of this report lies in the fact that the patient showed symptoms very late, when usually RP is diagnosed in adolescence which also progressed rapidly within 3 years to involve distant and far vision. The absence of any family history is also notable as it may indicate an autosomal recessive inheritance with low-penetrance or a sporadic mutation.

Mechano-electrical transduction components TMC1-CIB2 undergo a Ca2+-induced conformational change linked to hearing loss.

TMC1, a unique causative gene associated with deafness, exhibits variants with autosomal dominant and recessive inheritance patterns. TMC1 codes for the transmembrane channel-like protein 1 (TMC1), a key component of the mechano-electrical transduction (MET) machinery for hearing. However, the molecular mechanism of Ca2+ regulation in MET remains unclear. Calcium and integrin-binding protein 2 (CIB2), another MET component associated with deafness, can bind with Ca2+. Our study shows that TMC1-CIB2 complex undergoes a Ca2+-induced conformational change. We identified a vertebrate-specific binding site on TMC1 that interacts with apo CIB2, linked with hearing loss. Using an exvivo mouse organotypic cochlea model, we demonstrated that disruption of the calcium-binding site of CIB2 perturbs the MET channel conductivity. After systematically analyzing the hearing loss variants, we observed dominant mutations of TMC1 cluster around the putative ion pore or at the binding interfaces with CIB2. These findings elucidate the molecular mechanisms underlying TMC1-linked hearing loss.

Short and long‐read whole genome sequencing in inherited retinal diseases in finland

Genetic research can benefit from population isolates like Finland, as they tend to have a high concentration of deleterious alleles on a small number of low‐frequency variants. To investigate gene findings from the patients with inherited retinal disorders (IRD) in Finland, retrospectively collected data from the patients with IRDs treated between January 1st 2012, and December 31st 2020 at the Department of Ophthalmology, Helsinki University Hospital. Of the 638 patients who underwent genetic testing, 79% received a likely genetic diagnosis (504/638). The genetic findings corresponded to autosomal recessive (AR) inheritance in 242 patients, X‐linked (XL) in 158, autosomal dominant (AD) in 94, and mitochondrial inheritance in 22 patients. The most common genetic diagnosis was X‐linked retinoschisis as 17% (84/504) harbored pathogenic variants in RS1. The most common retinitis pigmentosa genes with causative variants were CERKL (8.5%, 43/504), RPGR (5.8%, 24/504), and EYS (5%, 25/504). CERKL variant c.375C>G, p.(Cys125Trp) and EYS c.1155T>A, p.(Cys385Ter) are frequent founder mutations. The Stargardt disease is less common than in other Western countries, the pathogenic variants in the ABCA4 gene were found in 24 patients. The genetic landscape of IRDs in Finland differs from other Western countries due to its specific isolated population history. The high yield of genetic findings is possibly explained by the enriched founder mutations in the population. One‐fifth of the patients lack genetic diagnosis, which might be due to shortages in the testing methods, i.e., non‐coding variants and complex structural genomic variants are missing. To address this problem, we have been utilizing the whole genome short‐ and long‐read sequencing methods to uncover new pathogenic variants. In the patients with presumable recessive inheritance and one pathogenic variant found, we have utilized short‐read genome sequencing to uncover regulatory regions and deep intronic variants. In two families with IRDs, we have found large structural variants in the RP1 and PRPH2 genes using Nanopore long‐read sequencing. In the future, we try to utilize the advantages of the population isolate to find unknown genes causing IRDs.

Leber congenital amaurosis: A clinical and genetic study from a tertiary eye care center.

To assess the clinical phenotypes and genetic mutations in patients with Leber congenital amaurosis (LCA) from a tertiary eye care center in India. Retrospective observational study. The study includes patients with a clinical diagnosis of LCA who underwent genetic testing from January 2016 to December 2021. The clinical exome of the patients was analyzed by targeted next-generation sequencing. The genetic variants found were classified as per standard American College of Medical Genetics and Genomics (ACMG) criteria and ClinVar database. There were 35 patients (19 females, 16 males) of LCA. Family history was positive in 29% (10/35) and a history of consanguinity was noted in 54% (19/35) of the patients. The mean presenting best-corrected visual acuity was 2.48 ± 0.59 logMAR. Retinal pigment epithelial abnormalities and macular involvement were seen in 83% (58/70) and 23% (16/70) of the eyes, respectively, at presentation. The most common causative genes for LCA in our cohort were: GUCY2D (20%, 7/35), CRB1 (14%, 5/35), RPE65 (11%, 4/35), RPGRIP1 (11%, 4/35), and LCA5 (9%, 3/35). Autosomal recessive inheritance was seen in 94% (33/35). Macular involvement at presentation was seen in CRB1 (3/5), NMNAT1 (2/2), and one each of RPE65, LCA5, and RDH12 patients. The genetic testing cost was reduced from 23,800 INR to 15,000 INR per test in the study duration. Genetic screening of LCA cases identified various genotypes, with GUCY2D being the most common. Increased awareness and reduced costs of genetic testing would benefit both patients and caregivers. With promising clinical trial outcomes, genotyping is crucial for better patient selection and treatment.

From spastic paraplegia to infantile neurodegenerative disorder: Expanding the phenotypic spectrum associated with biallelic SPAST variants.

Heterozygous pathogenic variants in SPAST are known to cause Hereditary Spastic Paraplegia 4 (SPG4), the most common form of HSP, characterized by progressive bilateral lower limbs spasticity with frequent sphincter disorders. However, there are very few descriptions in the literature of patients carrying biallelic variants in SPAST. Targeted Sanger sequencing, panel sequencing and exome sequencing were used to identify the genetic causes in 9 patients from 6 unrelated families with symptoms of HSP or infantile neurodegenerative disorder. We describe 5 patients with pure HSP with a variable age of onset, mostly in infancy, and 4 patients with profound intellectual disability and progressively worsening tetrapyramidal syndrome. The patients' parents, heterozygous carriers of pathogenic SPAST variants, included both asymptomatic carriers and patients with classic forms of SPG4. Biallelic variants of SPAST may explain cases of hereditary spastic paraplegia with autosomal recessive inheritance. Furthermore, some biallelic variants may also cause psychomotor regression with an infantile neurodegenerative disorder, associated with a tetrapyramidal syndrome, a new phenotype associated with the SPAST gene.

Hereditary Spastic Paraplegia Linked to Abnormal Splicing From an AIMP1 Missense Variant.

Hereditary spastic paraplegias (HSP) are a diverse group of neurodegenerative diseases characterized by lower limb spasticity and weakness. To date, over 80 genes have been associated with HSP, but many families remain without a molecular diagnosis. In this study, linkage analysis and whole-exome sequencing (WES) were performed to identify the causal gene in a HSP family with autosomal recessive inheritance. Multipoint linkage analysis revealed a maximum significant multipoint LOD score of 4.6 on chromosome 4. WES analysis focused on this region led to the identification of a homozygous missense variant in AIMP1 (c.223G>A). Minigene assays showed that the presumed missense variant in AIMP1 caused loss of the exon 3 donor splice site. Ultimately, this led to the use of an alternative splice site within the intron and the insertion of a premature stop codon. The identification of a novel AIMP1 causal variant contributes to the growing list of HSP genes. Furthermore, it shows that, considering also previous reported cases, disruption of AIMP1 causes a spectrum of disorders ranging from intellectual disability to more complex neurodegenerative diseases.

Pyloric web : Management of a neglected case of Gastric Outlet Obstruction

Pyloric atresia is an extremely rare cause of gastric outlet obstruction, constituting approximately 1% of all gastrointestinal atresias and occurring in about 1 in 100,000 live births. It is equally prevalent in males and females and may exhibit autosomal recessive inheritance. Clinically, it presents during infancy with non-bilious vomiting, abdominal distension, and failure to thrive. Type 1 pyloric atresia, characterized by a pyloric membrane with an opening, is exceptionally rare and may present later in childhood. We reported the case of a 5-year-old male with the history of recurrent non-bilious vomiting since the age of one year, which worsened over the preceding four months. Examination revealed visible peristalsis and upper abdominal fullness. Radiological findings suggested gastric outlet obstruction, and exploratory laparotomy confirmed Type 1 pyloric atresia. Surgical management involved excision of the pyloric web and Heineke-Mikulicz pyloroplasty. The child had an uneventful recovery and demonstrated significant improvement in weight and nutritional status at a 6-month follow-up. The diagnosis of pyloric atresia is challenging due to its rarity and similarity to other conditions like duodenal atresia or hypertrophic pyloric stenosis. Early diagnosis through clinical suspicion, radiological evaluation, and definitive surgical intervention is crucial to prevent complications such as aspiration pneumonia and metabolic imbalances. This case highlights the importance of considering pyloric atresia in children with recurrent vomiting and failure to thrive, even beyond infancy, and emphasizes the significance of prompt surgical management for favorable outcomes.

Rare Inherited Coagulation Deficiencies: A Single-Center Study

Background: Rare factor deficiency (RFD) is characterized by a deficiency of factor (F)I, FII, FV, FVII, FX, FXI, FXII, FXIII, or a combined deficiency of FV+FVIII or vitamin K-dependent factors. The prevalence of RFD ranges from 1/1,000,000 to 3,000,000. Combined deficiencies of vitamin K-related factors have been described in 30 families worldwide, and these patients can present with a wide range of clinical symptoms, from mucocutaneous bleeding to life-threatening symptoms such as central nervous system and gastrointestinal bleeding. Objective: This study aimed to contribute to the literature on RFD. Material and Methods: This retrospective study analyzed data from 43 children with RFD. Results: The most common factor deficiencies were FVII (n=13); whereas the other deficiencies were FI (n=1), FV (n=2), FV+FVIII (n=2), FX (n=6), FXI (n=5), FXII (n=9), FXIII (n=3), and vitamin K-dependent combined factor deficiency (n=2). Acute and severe bleeding was controlled by treatment in 6 patients, and 12 patients with recurrent bleeding symptoms received prophylaxis. RFDs were more common in regions with high rates of consanguineous marriage, and in our study, 16 (16/43) of the cases were found to have consanguineous marriages between parents. Conclusions: It is important to improve genetic counseling and access to testing for family members with RFD due to autosomal recessive inheritance. Delays in diagnosis and treatment and lack of adequate prevention are important risk factors for life-threatening bleeding.

Beyond the "Dominant" and "Recessive" Patterns of Inheritance.

This study aimed to investigate whether genes with different modes of inheritance differ in the presence of promoter-enriched CGI loci. For each autosomal chromosome, the author searched for variations in the total number of diseases' phenotypes with autosomal dominant (AD) and recessive (AR) inheritance for a list of promoter-poor CGI (CGI-) and promoter-enriched CGI (CGI+) genes using the OMIM database. Then, the CGI- and CGI+ genes displaying random allelic or bi-allelic expression were examined. The author evaluated whether there was a distinct distribution of AD and AR diseases in the groups of chromosomes based on their SNP hotspot density. The same analysis was conducted for the X chromosome. The SPSS statistical package was utilized. The distribution of AD and AR diseases between CGI- and CGI+ bi-allelic genes significantly differed in autosomal chromosomes 6 and 17, which show intermediate SNP hotspot density. Additionally, a statistically significant difference was observed in AD and AR diseases in the remaining autosomal chromosomes with low SNP hotspots between their randomly allelic expressed CGI- and CGI+ genes. Specifically, AD diseases were related to CGI- genes, while AR diseases were associated with CGI+ genes. In the X chromosome, X-linked dominant (XLD) diseases were mainly found in CGI+ genes, and X-linked recessive (XLR) diseases were found in CGI- genes, regardless of the X-inactivation process. It is essential to study inheritance and classify genetic variants in a more stochastic way than the terms "Dominant" and "Recessive," and their derivatives, such as "Codominant" and "Incomplete Dominant," are applied in Mendelian and non-Mendelian inheritance. This concept may further explain the "Reduced Penetrance" and "Variable Expressivity" in certain human diseases. All the above suggests a need to reassess how genetic and epigenetic data are studied and utilized for genetic counseling or precision medicine.

Patients with a Wide Range of Disorders Related to WFS1 Gene Variants: Novel Mutations and Genotype-Phenotype Correlations.

Background:WFS1-spectrum disorders are caused by a mutation in the WFS1 gene. The term includes a wide range of rare disorders, from the most severe Wolfram syndrome with autosomal recessive inheritance to milder clinical manifestations with a single causative variant in the WFS1 gene, such as Wolfram-like syndrome, low-frequency sensorineural hearing loss (LFSNHL), isolated diabetes mellitus (DM), nonsyndromic optic atrophy (OA), and isolated congenital cataracts. Methods: The aim of this study was to evaluate genotype-phenotype correlations in Polish patients with WFS1-spectrum disorders. The study group constituted 22 patients (10 F; 12 M), including 10 patients (3 F; 7 M) referred to the Outpatient Clinic for Rare Diseases in Children and Adolescents and Diabetogenetics between 2019 and 2024 with clinical symptoms suggestive of WFS1-spectrum disorders, and 12 of their first-degree relatives (7 F; 5 M) from 10 families in Poland. Molecular testing was performed using tNGS (Targeted Next Generation Sequencing; Illumina) and analyzed for variants in the WFS1 gene. Results: Thirteen different variants in the WFS1 gene were found in 22 individuals (10 patients and family members), including the identification of two new variants (c.1535T>C and c.2485C>G). All patients had hyperglycemia or DM, hearing impairment, OA, or a combination of these symptoms. Four patients in the study group were diagnosed with Wolfram syndrome and all were compound heterozygotes for variants in the WFS1 gene. Conclusions: The evaluation of molecular characteristics in combination with clinical symptoms broadens the understanding of WFS1-spectrum disorders and allows more accurate management and prognosis for patients with this diagnosis.

Analysis of a Chinese pedigree with female infertility due to WEE2 gene c.495del homozygous frameshifting variant induced fertilization disorder

To explore the genetic basis for a patient with repeated fertilization failure during assisted reproductive therapy, and to identify the source and mode of mutation. A couple treated at the Center for Reproductive Medicine, Gansu Provincial Maternal and Child Health Care Hospital in January 2024 for infertility with incomplete left tube obstruction was selected as the study subject. Relevant clinical data was collected. The couple was subjected to whole exome sequencing (WES), and the candidate variant was verified by Sanger sequencing of their family members and bioinformatic analysis. WES has identified a homozygous c.495del frameshifting mutation of the WEE2 gene in the female partner, whilst no relevant variant was suspected in the male partner. The elder brother of the female partner was homozygous for the above variant, while her parents, maternal and paternal aunts, uncle, grandmother, and grandmother were heterozygous for it. Based on the guidelines from the American College of Medical Genetics and Genomics, above variant was rated to be pathogenic. The homozygous c.495del frameshifting mutation of the WEE2 gene probably underlay the oocyte fertilization disorder in this couple, which has conformed to an autosomal recessive inheritance.

FC22 Assessment of pustular psoriasis genes in generalized and palmoplantar pustular psoriasis suggest transethnic differences in disease susceptibility, an oligogenic inheritance in both psoriatic subtypes and an involvement of purinergic receptors

Abstract Generalized (GPP) and palmoplantar pustular psoriasis (PPP) are psoriatic subtypes affecting fewer psoriatic patients but often more severely than common psoriasis vulgaris. While several susceptibility genes have been identified in GPP mainly in Africa and Europe, there is currently a lack of established risk factors for PPP. Recently, P2RX7 variants were suggested to contribute to chronic non-bacterial osteomyelitis (CNO), a clinically overlapping disease. In order to estimate the effect sizes of susceptibility variants in GPP and CNO genes, we assessed 195 exome/ genome sequences of GPP and PPP systematically and performed a literature search for published datasets of European pustular psoriasis patients. Depending on the reported state of disease-variants, we compared allele or genotype frequencies to those of controls. In the case of bi-allelic variants, we considered ∼4900 individuals in whom allele dosage could be determined. Meta-analysis in GPP revealed significant effect sizes for IL36RN and MPO variants in European carriers of mono-, but especially of bi-allelic variants [IL36RN: odds ratio (95% confidence interval) = 334.2 (106.5–1599.2); MPO: 73.7 (16.5–328.5)], as expected for a monogenic/ oligogenic disease like GPP. Nine PPP patients (8%) carried a coding variant in either IL36RN or MPO, one additional individual with disease-contributing variants in both IL36RN and MPO suggests that oligogenic inheritance might also be relevant in PPP. Not a single PPP patient, but five GPP patients were identified to carry P2RX7 missense variants predicted/shown to have an impact on the signalling pathway; notably, one of the latter patients carried two variants, suggesting autosomal recessive inheritance. Putative disease variants in AP1S3 were not associated, while SERPINA3 variants were too rare to perform reliable comparisons. We did not analyse CARD14, as there are numerous missense variants and the classification of many missense variants into different ACMG categories is rather arbitrary. Our study indicates a continuum of GPP-PPP-CNO and a significant contribution of IL36RN and MPO variants on disease susceptibility in bi-allelic states and in European GPP patients, less commonly in PPP. The lack of association of pustular psoriasis with BTN3A3 in European patients and with MPO variants in Asian patients suggests transethnic differences in disease susceptibility. The overall allele frequencies of up to 4.5% of variants in AP1S3 and BTN3A3 in certain populations and a considerable frequency of homozygous, healthy carriers of risk alleles in BTN3A3 and AP1S3 render an impact on disease susceptibility less likely. As variants in known disease genes affect <40% of GPP patients and a low percentage in PPP, there is a high need to elucidate the molecular basis of pustular psoriasis, in order to offer more targeted, individualized therapy.

Phenotype and genetic spectrum of six Indian patients with bestrophinopathy.

The aim of this study is to describe genotype and phenotype of patients with bestrophinopathy. The case records were reviewed retrospectively, findings of multimodal imaging such as color fundus photograph, optical coherence tomography (OCT), fundus autofluorescence, electrophysiological, and genetic tests were noted. Twelve eyes of six patients from distinct Indian families with molecular diagnosis were enrolled. Exon 4 of BEST1 was mutated in 3 cases, while exons 2, 3, and 7 in others. Deletion is seen in Exon 7 and missense mutation in other exons. Sporadic autosomal dominant and recessive inheritance was observed in these families. Two patients had primary angle closure glaucoma with a history of consanguineous marriage and glaucoma in the family. Based on our findings, multifocal vitelliform subretinal deposits were the most common fundus finding in patients with autosomal recessive mutation while macular vitelliform lesion was seen with sporadic or autosomal dominant mutation; however, cosegregation analysis was not done. Baseline OCT showed macular and extramacular subretinal exudates, subretinal fluid, intraretinal cystic and schitic spaces, and thickened photoreceptors outer segment tips. Two patients developed abnormal vasculature and focal choroidal excavation in OCT. A severe reduction in the electro-oculogram Ardens ratio was noted while electroretinography was normal. Bestrophinopathy has a varied presentation with complex genotype-phenotype relationships. OCT is a noninvasive tool for monitoring and prognostication. Genetic testing of other family members should be facilitated.