Autosomal Recessive Condition Research Articles

The First Fetal Case of Shwachman-Diamond Syndrome Mimicking Vascular Growth Restriction.

Shwachman-Diamond Syndrome (SDS) is a rare autosomal recessive genetic condition with 90% of cases associated with biallelic pathogenic variants in the Shwachman-Bodian-Diamond Syndrome (SBDS) gene on chromosome 7q.11.21. SDS belongs to ribosomopathies since SBDS gene encodes a protein involved in ribosomal maturation. Its phenotypic postnatal hallmark features include growth delay, bone marrow failure, exocrine pancreatic insufficiency, and skeletal abnormalities. We report a first fetal case of Shwachman-Diamond syndrome and extend its phenotype before birth. The clinical features mimicked vascular growth restriction with FGR and shortened long bones, associated with abnormal Doppler indices. Non-restricted fetal autopsy after termination of pregnancy allowed deep phenotyping disclosing the features of fetal skeletal dysplasia. Post-fetopathological trio exome sequencing identified biallelic pathogenic variants in the SBDS gene. Genotype-phenotype correlations confirmed the diagnosis and enabled an adequate genetic counseling of the parents. Our case is another example of the positive impact of fetal autopsy coupled with post-fetopathological genomic studies, even in the cases that were hitherto classified as maternal or fetal vascular malperfusion.

First author gender equality trends in publication of mitochondrial neuro gastrointestinal encephalopathy-MNGIE disease

Mitochondrial neuro gastrointestinal encephalopathy (MNGIE) is a rare autosomal recessive genetic condition caused mainly by thymidine phosphorylates (TP) deficiency and TYMP mutations. Gender equality in scientific publishing is crucial for fostering inclusive practices and promoting diversity in research. This research article conducted a bibliometric analysis using PubMed as the primary data source. The analysis focused on studying the trends and patterns of first author gender equality in the publication of MNGIE disease. The methodology involved data collection, article screening, gender determination using the Namsor app, statistical analysis using R software, and visualization of findings through graphs created with DataWrapper. Our study utilized PubMed as the primary data source, covering the period from 1993 to 2022, and included 224 articles. The findings revealed that 57.6% of first authors were male, while 42.4% were female. Furthermore, the analysis of gender trends based on countries revealed that the Netherlands had the most favorable gender ratio. It revealed a significant association present between the first author’s gender and country. Additionally, selected journals exhibited a favorable gender ratio, with a 1:1 female-to-male ratio in nine out of ten journals examined. ARIMA model predicted that by 2027, approximately 160 publications would have male whereas around 120 publications would have female first authors. Our study highlights the gender discrepancies in first authorship within the context of MNGIE publications and provides insights into the representation of women in medical research. Efforts should be made to address these inequalities and promote gender equality in scientific publishing.

Cerebral involvement in sitosterolemia

BackgroundSitosterolemia, an autosomal recessive condition, is characterized by impaired metabolism of plant sterols. Clinical symptoms include skin xanthoma, premature atherosclerotic disease, arthritis, and unexplained hematological abnormalities. However, there is a dearth of studies on sitosterolemia-related brain damage.MethodsThis study focused on the family of two sitosterolemia patients who presented with severe hypercholesterolemia and xanthoma. Radiological examinations, biopsies, whole-exome sequencing (WES), and plant sterol tests were conducted.ResultsThe index patient, a 66-year-old female, initially exhibited weakness in both lower limbs and later developed urinary and fecal incontinence. Neuroimaging showed that the falx of the brain had irregular fusiform thickening. Significant tissue edema was observed around the lesions in the bilateral frontal-parietal lobes. Pathological analysis of the biopsied brain lesion revealed extensive cholesterol crystal deposition and lymphocyte infiltration in the matrix. The index patient who experienced cerebral impairment and her sister both carried two compound heterozygous variants in ATP binding cassette transporter G5 (ABCG5). These included the nonsense variants NM_022436: c.751 C > T (p.Q251X) in exon 6 and NM_022436: c.1336 C > T (p.R446X) in exon 10. A notable increase in plant sterol levels was observed in the younger sister of the index patient.ConclusionThis study highlights a previously unreported neurological aspect of sitosterolemia. Imaging and pathology findings suggest that cholesterol crystals may be deposited in connective tissues such as the cerebral falx and pia mater through blood circulation.

A Five-Year Review of Newborn Screening for Spinal Muscular Atrophy in the State of Utah: Lessons Learned.

Spinal muscular atrophy (SMA) is an autosomal recessive condition characterized by alpha motor neuron degeneration in the spinal cord anterior horn. Clinical symptoms manifest in the first weeks to months of life in the most severe cases, resulting in progressive symmetrical weakness and atrophy of the proximal voluntary muscles. Approximately 95% of SMA patients present with homozygous deletion of the SMN1 gene. With multiple available therapies preventing symptom development and slowing disease progression, newborn screening for SMA is essential to identify at-risk individuals. From 2018 to 2023, a total of 239,844 infants were screened. 13 positive screens were confirmed to have SMA. An additional case was determined to be a false positive. We are not aware of any false-negative cases. All patients were seen promptly, with diagnosis confirmed within 1 week of the initial clinical visit. Patients were treated with nusinersen or onasemnogene abeparvovec. Treated patients with two copies of SMN2 are meeting important developmental milestones inconsistent with the natural history of type 1 SMA. Patients with 3-4 copies of SMN2 follow normal developmental timelines. Newborn screening is an effective tool for the early identification and treatment of patients with SMA. Presymptomatic treatment dramatically shifts the natural history of SMA, with most patients meeting appropriate developmental milestones. Patients with two copies of SMN2 identified through newborn screening constitute a neurogenetic emergency. Due to the complexities of follow-up, a multidisciplinary team, including close communication with the newborn screening program, is required to facilitate timely diagnosis and treatment.

Novel GNAI3 mutation in a Chinese family with auriculocondylar syndrome and treatment of severe dentofacial deformities: a 5-year follow-up case report

BackgroundAuriculocondylar syndrome (ARCND) is an extremely rare autosomal dominant or recessive condition that typically manifests as question mark ears (QMEs), mandibular condyle hypoplasia, and micrognathia. Severe dental and maxillofacial malformations present considerable challenges in patients’ lives and clinical treatment. Currently, only a few ARCND cases have been reported worldwide, but most of them are related to genetic mutations, clinical symptoms, and ear correction; there are few reports concerning the treatment of dentofacial deformities.Case presentationHere, we report a rare case of ARCND in a Chinese family. A novel insertional mutation in the guanine nucleotide-binding protein alpha-inhibiting activity polypeptide 3 (GNAI3) was identified in the patient and their brother using whole-exome sequencing. After a multidisciplinary consultation and examination, sequential orthodontic treatment and craniofacial surgery, including distraction osteogenesis and orthognathic surgery, were performed using three-dimensional (3D) digital technology to treat the patient’s dentofacial deformity. A good prognosis was achieved at the 5-year follow-up, and the patient returned to normal life.ConclusionsARCND is a monogenic and rare condition that can be diagnosed based on its clinical triad of core features. Molecular diagnosis plays a crucial role in the diagnosis of patients with inconspicuous clinical features. We present a novel insertion variation in GNAI3, which was identified in exon 2 of chromosome 110116384 in a Chinese family. Sequential therapy with preoperative orthodontic treatment combined with distraction osteogenesis and orthognathic surgery guided by 3D digital technology may be a practical and effective method for treating ARCND.

Derivation of two iPSC lines (KAIMRCi004-A, KAIMRCi004-B) from a Saudi patient with Biotin-Thiamine-responsive Basal Ganglia Disease (BTBGD) carrying homozygous pathogenic missense variant in the SCL19A3 gene

The neurometabolic disorder known as biotin-thiamine-responsive basal ganglia disease (BTBGD) is a rare autosomal recessive condition linked to bi-allelic pathogenic mutations in the SLC19A3 gene. BTBGD is characterized by progressive encephalopathy, confusion, seizures, dysarthria, dystonia, and severe disabilities. Diagnosis is difficult due to the disease’s rare nature and diverse clinical characteristics. The primary treatment for BTBGD at this time is thiamine and biotin supplementation, while its long-term effectiveness is still being investigated. In this study, we have generated two clones of induced pluripotent stem cells (iPSCs) from a 10-year-old female BTBGD patient carrying a homozygous mutation for the pathogenic variant in exon 5 of the SLC19A3 gene, c.1264A > G (p.Thr422Ala). We have confirmed the pluripotency of the generated iPS lines and successfully differentiated them to neural progenitors. Because our understanding of genotype–phenotype correlations in BTBGD is limited, the establishment of BTBGD-iPSC lines with a homozygous SLC19A3 mutation provides a valuable cellular model to explore the molecular mechanisms underlying SLC19A3-associated cellular dysfunction. This model holds potential for advancing the development of novel therapeutic strategies.

P-508 Management of incidental findings after preconception expanded carrier screening: identifying genetic predispositions to cancer and metabolic conditions in 8010 screened ART patients

Abstract Study question How do individuals and fertility clinics navigate incidental findings from Expanded Carrier Screening (ECS) in reproductive decision-making? Summary answer Incidental ECS findings prompted varied responses from patients and gamete donors, influencing diverse reproductive choices and underscoring the pivotal role of pre-test genetic counseling. What is known already ECS aims to assess reproductive risk in the general population for specific autosomal recessive and X-linked conditions. These manifest in infancy or early childhood and impact life expectancy or the quality of life. ECS results may guide interventions to avoid affected pregnancies, such as the implementation of preimplantation genetic testing of embryos (PGT-M). Additionally, ECS has the potential to uncover incidental findings with significant health implications, such as an elevated cancer risk or diagnosis. However, the lack of comprehensive reporting guidelines necessitates meticulous analysis to ensure effective clinical guidance for these individual findings. Study design, size, duration This retrospective descriptive study assessed the results of ECS tests performed in 5475 patients and 2535 oocyte and semen donors from four different fertility clinics between July 2017 and December 2023. ECS reports with incidental findings in the ATM, FH or LDLR genes were identified and further examined. We calculated individual and reproductive risks for affected individuals and recorded the subsequent clinical management pertaining to each case. Participants/materials, setting, methods Pre-test counselling was offered to both patients and gamete donors before consenting to ECS. Testing was outsourced to an external genetics laboratory using a panel of 309 genes analyzed through next generation sequencing and complementary molecular techniques. The laboratory reported pathogenic and likely pathogenic variants that were subsequently manually reviewed by an internal genetics committee. Personal and reproductive risks were assessed for each case and genetic counseling was provided in a subsequent meeting. Main results and the role of chance Genetic variants in ATM, FH, or LDLR genes were reported in 134 out of 8010 individuals undergoing ECS (1.67%). Among these, 108 variants were identified in patients: 53.7% (n = 58) in ATM, 19.4% in FH (n = 21), and 26.8% (n = 29) in LDLR. Out of the variants identified as incidental findings, 20/108 were actionable and eligible for PGT-M: 19 were associated with an increased risk for breast cancer and 1 for renal cancer. After being informed of the findings and their implications, 7/20 couples opted to revoke treatment as, according to internal policies, PGT-M was mandatory in such cases; 6/20 couples chose to undergo double gamete donation; 6/20 couples opted for PGT-M. Patients with pathogenic variants in LDLR linked to autosomal dominant inheritance for familial hypercholesterolemia (20/108, 18.5%), received follow-up guidelines and family genetic counseling. Pathogenic variants in ATM, FH, and LDLR were also identified in 26 gamete donors (24 oocyte donors and 2 sperm donors). Following internal review, 14 of these variants were considered incidental findings with an increased risk for breast cancer (13/14) or familial hypercholesterolemia (1/14), leading to the exclusion of these potential donors from the donation program. Limitations, reasons for caution The reproductive handling of incidental findings in our population relies on subjective decisions by the internal genetics committee, which may evolve with scientific advancements and recommendations from professional societies. Follow-up data on long-term reproductive outcomes are lacking. Wider implications of the findings This study reveals the diverse reproductive decisions made in response to incidental findings, underscoring the importance of pre-test genetic counseling. Our findings also highlight the subsequent impact on fertility programs, which may lead to the exclusion of gamete donors or patients choosing to revoke treatment. Trial registration number Not Applicable

P-569 Reciprocal expanded carrier screening for intended parents and gamete donors: experience of a global surrogacy support network

Abstract Study question Is expanded carrier screening an effective tool to identify carriers of clinically relevant genes and determine the reproductive risk between a donor and recipient pair? Summary answer This study has determined that there is a strong rationale for performing matching according to expanded carrier screening results, especially for gamete donor programs. What is known already Carrier screening (CS) identifies carriers of autosomal recessive (AR) and/or X-linked (XL) genetic conditions to establish reproductive risk. If both partners (egg and sperm providers) carry a pathogenic variant in the same gene (co-carriage), there is 25% risk that offspring will be affected. The same risk is present for egg providers who carry an XL disorder. In expanded carrier screening (ECS), many clinically relevant conditions are screened simultaneously using a single-panel approach. The implementation of ECS is becoming commonplace across gamete donor banks. Providing recipients with a matching panel is key in determining reproductive risk and suitable treatment options. Study design, size, duration In this retrospective review, data was collected for 104 gamete recipients and 31 gamete donors who underwent ECS between March 2021-January 2024. ECS was provided through a single genetic testing laboratory, using a whole exome sequencing (WES) platform. The panel used for the gamete donors/recipients consisted of approximately 500 AR genes; optional analysis of 66 X-Linked genes was available for biologically female donors/recipients. Participants/materials, setting, methods In total, 104 gamete recipients were screened against one or more donor(s) using the same ECS panel. All donors/recipients underwent testing in a clinical setting and received pre/post-test genetic counselling, where required. The testing laboratory provided the referring clinician with the results for each individual. Matching was overseen by My Surrogacy Journey and the relevant donor bank. Donor-recipient match reports were requested from the testing laboratory. Individual and matched reports were used for this review. Main results and the role of chance In total, 76.9% (80/104) of gamete recipients presented with a positive result in at least one clinically relevant gene that could have an impact on reproductive planning. Between the 80 positive gamete recipients, 177 gene variants were carried; variant classification was available for 132 variants (74.6%). The majority of gene variants carried were classified as pathogenic (59.9%), meaning that these variants are associated with causing disease. Most frequently, recipients were carriers of a variant in 1-3 genes (1 gene: 36.3%; 2 genes: 27.5%; 3 genes: 22.5%). In addition to this, 77.4% (24/31) of gamete donors were identified to carry a variant in at least one clinically relevant gene, which includes one egg donor (3.2%; 1/24) who was a carrier of an XL condition. This meant that despite the lack of co-carriage in the AR gene(s) of interest, the recipient could not proceed with this donor due to the associated risk (25%). Of the 43 recipients matched with a donor, 9.3% (4/43) showed a high reproductive risk (25%) due to their reciprocal matching results. This expanded carrier screening strategy demonstrates significant utility in identifying positive carrier status and supporting donor-recipient matching programmes by determining high risk reproductive pairs. Limitations, reasons for caution This study was retrospective in nature. The majority of recipients were Caucasian (∼80% of cases). Ethnic groups are not homogenous; there can be significant genetic, cultural, and environmental diversity between/within ethnic groups. Decision outcome data should be collected to improve this work. Wider implications of the findings The findings from this analysis suggest that there is a strong rationale for performing donor-recipient matching using an ECS approach. Increasing awareness and accessibility of ECS in this setting should be a global initiative, with the ultimate aim of reducing the burden of genetic disease in donor-conceived offspring. Trial registration number N/A

Shortcomings of ethnicity-based carrier screening for conditions associated with Ashkenazi Jewish ancestry

PurposeCarrier screening identifies reproductive risk for autosomal recessive and X-linked genetic conditions. Currently, some medical society guidelines continue to recommend ethnicity-based carrier screening for conditions associated with Ashkenazi Jewish (AJ) ancestry. We assessed the utility and limitations of these guidelines in a large, ethnically and genetically diverse cohort of genotyped individuals. MethodsWe characterized the self-reported ethnicity and genetic ancestry of over 110,000 consenting research participants identified as heterozygous for pathogenic variants associated with 15 autosomal recessive conditions recommended by the American College of Obstetricians and Gynecologists for screening in individuals of AJ descent. ResultsOut of 7.2 million research participants, 116,517 research participants were identified as heterozygous for pathogenic variants associated with 15 conditions evaluated. The majority (54.9%) of heterozygotes did not report qualifying ethnicity under American College of Obstetricians and Gynecologists ethnicity-based screening guidelines. Approximately half (51.3%) of all individuals heterozygous for pathogenic variants in genes associated with 1 or more conditions recommended to be screened exclusively in individuals of AJ descent had <20% computed AJ ancestry. ConclusionEthnicity-based carrier screening leads to the under detection of heterozygotes and associated reproductive risk for conditions historically associated with AJ ancestry.

A rare bleeding disorder with severe haemorrhagic manifestation

Factor V is a major part of the coagulation system and maintains a balance in pro-coagulant and anticoagulant pathways. Any deficiency or mutation can lead to disequilibrium in coagulation. Factor V deficiency can be congenital or acquired. Congenital factor V deficiency (parahemophilia or Owren’s disease) is a rare autosomal recessive condition. We present a case of an adolescent unmarried girl presenting with an acute abdomen and deranged coagulation parameters. It was confirmed that the bilateral haemorrhagic ovarian cysts and hemoperitoneum were due to factor V deficiency. In her case, the bleeding was likely due to a ruptured corpus luteum during ovulation. She was successfully managed conservatively with red cells and fresh frozen plasma transfusions, tranexamic acid and combined oral contraceptive pills (COCP) with instructions to continue the use of COCP to prevent such bleeding manifestations.

Managing risks for genetic conditions in donor sperm treatment: current practices in Belgian fertility clinics

Research questionHow do fertility clinics in Belgium manage risks for genetic conditions in donor sperm treatment? DesignAn electronic questionnaire was distributed to all fertility clinics in Belgium in June 2023, focusing on treatments with anonymous sperm donors from 2018 to 2022. Responses from 15 clinics were analyzed anonymously with IBM SPSS statistics. ResultsAll clinics assessed donor risks, including a personal and family history, conventional karyotyping, and (for 83% of the clinics) carrier screening for common autosomal recessive conditions. For recipients, 58% of the clinics relied only on a personal and family history. Despite efforts, the suspicion or detection of genetic conditions in donor sperm treatment was prevalent, with 9.4 adverse events reported per 100 children born. When adverse events occurred, most clinics (58%) would not inform the donor if no additional genetic testing was needed. Around 1 in 4 (27%) clinics always informed recipients about an adverse event possibly related to their donor. An equal number (27%) categorically rule out the use of sperm from a donor after an adverse event is traced back to his DNA, and 53% would not consider using the donor when the adverse event was not genetically confirmed. For the other clinics, deciding when to disclose new genetic risk information or when to allow the use of a donor linked to an adverse event is a complex matter involving different considerations. ConclusionWhile suspected or detected genetic conditions linked to donor treatments were common, there was wide variation in how Belgian clinics prevent and manage these situations.

Novel TRPV6 variant linked with transient neonatal hyperparathyroidism

BackgroundHereditary transient neonatal hyperparathyroidism (TNHP) is a rare autosomal-recessive condition caused by variants in TRPV6 gene which encodes for a transient maternal–fetal calcium transport channel. This is characterized by interference with placental maternal–fetal calcium transport causing fetal calcium deficiency. It primarily manifests as defective bone mineralization, narrow and bell-shaped thorax, bone fractures and short bones at birth. The current study aimed to describe a novel TRPV6 variant linked with TNHP in an Indian family and the review of literature.Case presentationThe proband is a term female neonate with fetal growth restriction born to a third-degree consanguineous couple. She was noted to have diffuse defective bone mineralization, narrow and bell-shaped thoracic cavity, short bones and curved ribs without any bone fractures. The first pregnancy was affected with similar features in the fetus and had been terminated. Parental whole-exome sequencing suggested heterozygous missense variant in exon 12 of the TRPV6 gene (c.1585G > A, p.Asp529Asn) in both the parents. The proband required non-invasive respiratory support for ten days in neonatal intensive care unit. She had low calcium and high parathyroid hormone (PTH) and alkaline phosphatase (ALP) levels. She received calcium, phosphorus and vitamin D supplements for three months leading to normalization of serum PTH and ALP levels. Whole-exome sequencing of the proband suggested a homozygous missense variant in exon 12 of the TRPV6 gene (p.Asp529Asn; ENST00000359396.9) that results in the amino acid substitution of asparagine for aspartic acid at codon 529. To the best of author’s knowledge, this is the twelfth case of TNHP reported in literature. The novel variant of TRPV6 gene present in this family has not been reported earlier.ConclusionOur finding broadens the genotypic spectrum of TNHP.

OTULIN-related conditions: Report of a new case and review of the literature using GenIA

OTULIN encodes an eponymous linear deubiquitinase (DUB) essential for controlling inflammation as a negative regulator of the canonical NF-κB signaling pathway via the regulation of M1-Ub dynamics. Biallelic loss-of-function (LOF) mutations in OTULIN cause an autosomal recessive condition named Otulin-Related Autoinflammatory Syndrome (ORAS), also known as Otulipenia or AutoInflammation, Panniculitis, and Dermatosis Syndrome (AIPDS). Monoallelic OTULIN LOF, also known as OTULIN Haploinsufficiency (OHI) or Immunodeficiency 107 (IMD107), has been linked to an incompletely penetrant, dominantly inherited susceptibility to invasive Staphylococcal infections. At the same time, a recent novel ORAS-like inflammatory syndrome was described in association with a heterozygous missense mutation that appears to exert dominant negative (DN) effects. In this manuscript, we report the identification of a novel homozygous missense mutation, c.595 T > A; p.(Trp199Arg), in a Moroccan infant with an ORAS phenotype and provide experimental evidence for its pathogenicity. We go on to systematically review the literature for OTULIN-associated conditions by using the GenIA database (www.geniadb.net) to collect, extract and harmonize all clinical, laboratory and functional data for published patients and variants. Our comprehensive synthesis of genotypic, phenotypic, and mechanistic data enables a more in-depth view of the diverse mechanisms and pathways by which the OTULIN pathogenic variants may lead to human immune disease. This review may help variant classification activities and inform future variant evaluation, as well as the development of diagnostic and management guidelines. It also identifies current knowledge gaps and raises additional questions warranting future investigation.

Molecular genetic analysis of candidate genes for glutaric aciduria type II in a cohort of patients from Queensland, Australia

Glutaric aciduria type II (GAII) is a heterogeneous genetic disorder affecting mitochondrial fatty acid, amino acid and choline oxidation. Clinical manifestations vary across the lifespan and onset may occur at any time from the early neonatal period to advanced adulthood. Historically, some patients, in particular those with late onset disease, have experienced significant benefit from riboflavin supplementation. GAII has been considered an autosomal recessive condition caused by pathogenic variants in the gene encoding electron-transfer flavoprotein ubiquinone-oxidoreductase (ETFDH) or in the genes encoding electron-transfer flavoprotein subunits A and B (ETFA and ETFB respectively). Variants in genes involved in riboflavin metabolism have also been reported. However, in some patients, molecular analysis has failed to reveal diagnostic molecular results. In this study, we report the outcome of molecular analysis in 28 Australian patients across the lifespan, 10 paediatric and 18 adult, who had a diagnosis of glutaric aciduria type II based on both clinical and biochemical parameters. Whole genome sequencing was performed on 26 of the patients and two neonatal onset patients had targeted sequencing of candidate genes. The two patients who had targeted sequencing had biallelic pathogenic variants (in ETFA and ETFDH). None of the 26 patients whose whole genome was sequenced had biallelic variants in any of the primary candidate genes. Interestingly, nine of these patients (34.6%) had a monoallelic pathogenic or likely pathogenic variant in a single primary candidate gene and one patient (3.9%) had a monoallelic pathogenic or likely pathogenic variant in two separate genes within the same pathway. The frequencies of the damaging variants within ETFDH and FAD transporter gene SLC25A32 were significantly higher than expected when compared to the corresponding allele frequencies in the general population. The remaining 16 patients (61.5%) had no pathogenic or likely pathogenic variants in the candidate genes. Ten (56%) of the 18 adult patients were taking the selective serotonin reuptake inhibitor antidepressant sertraline, which has been shown to produce a GAII phenotype, and another two adults (11%) were taking a serotonin-norepinephrine reuptake inhibitor antidepressant, venlafaxine or duloxetine, which have a mechanism of action overlapping that of sertraline. Riboflavin deficiency can also mimic both the clinical and biochemical phenotype of GAII. Several patients on these antidepressants showed an initial response to riboflavin but then that response waned. These results suggest that the GAII phenotype can result from a complex interaction between monoallelic variants and the cellular environment. Whole genome or targeted gene panel analysis may not provide a clear molecular diagnosis.

Congenital hallux valgus occurs in Fibrodysplasia Ossificans Progressiva and BMPR1B-associated dysplasia: an important distinction

BackgroundFibrodysplasia Ossificans Progressiva (FOP; OMIM #135100) is an ultrarare genetic disorder characterised by congenital bilateral hallux valgus (CBHV), intermittent soft tissue swellings and progressive heterotopic ossification. We report a three-month-old girl with great toe abnormalities similar to FOP, in whom comprehensive clinical workup and genetic investigations illustrates an alternative diagnosis.Case presentationA three-month-old girl presented with CBHV. The antenatal period was unremarkable, she was born by spontaneous vaginal delivery with an uneventful subsequent course, except for maternal concern of her bent toes which received reassurance from several health professionals. Her mother’s persisting concerns were explored via the internet and social media leading her to request referral to an expert bone centre for consideration of FOP. On examination, she was thriving, there was no dysmorphism, subcutaneous lumps, skeletal or extra-skeletal deformity except for shortened great toes with lateral deviation of the proximal and distal phalanges. FOP was a feasible diagnosis, for which CBHV is highlighted as an early sign. A cautionary potential diagnosis of FOP was counselled, including advice to defer intramuscular immunisations until genetic results available. Genetic investigation was undertaken through rapid whole genomic sequencing (WGS), with analysis of data from a skeletal dysplasia gene panel, which demonstrated no ACVR1variants. The only finding was a heterozygous variant of unknown significance in BMPR1B (c1460T>A, p.(Val487Asp)), which encodes a bone morphogenic receptor involved in brachydactyly syndromes A1, A2 and D and acromesomelic dysplasia 3 (only the latter being an autosomal recessive condition).ConclusionThis report highlights that CBHV serves as a vital diagnostic indicator of FOP and affected infants should be considered and investigated for FOP, including precautionary management whilst awaiting genetic studies. The second educational aspect is that CBHV may not represent a generalised skeletal disorder, or one much less significant than FOP. Receptor-ligand BMP and Activins mediated interactions are instrumental in the intricate embryology of the great toe. Recognition of non-FOP conditions caused by alterations in different genes are likely to increase with new genomic technology and large gene panels, enhancing understanding of bone signaling pathways.

Prenatal exome sequencing for morphologically normal fetus: Should we be doing it?

We aimed to investigate the yield of prenatal exome sequencing (pES) in morphologically normal fetuses. This retrospective study analyzed 254 families with morphologically normal fetuses who underwent prenatal trio exome sequencing based on parental request between September 2020 and October 2023. Overall, abnormal findings were detected in 8 families (3.1%, 8/254) by pES. Among these, 6 families (2.3%, 6/254) were found to have fetuses affected with monogenic disorders (2 autosomal recessive conditions and 4 autosomal dominant conditions), while 2 families (0.8%, 2/254) were incidentally found to be couples at risk of having a future pregnancy with a recessive condition. Among the six fetuses detected with monogenic disorders, two fetuses carried a de novo variant in OPA1 and NF1, which are known to cause Optic atrophy 1 and Neurofibromatosis, respectively. One fetus was detected with a maternally inherited variant in PKD2 related to polycystic kidney disease 2 (not known to the mother until then). One fetus was detected with a maternally inherited variant in SDHB associated with Pheochromocytoma. Two fetuses carried compound heterozygous variants in NAGLU and GJB2 associated with Mucopolysaccharidosis type IIIB and Deafness, respectively. In the 2 families where parents were found to be carriers but the fetuses were unaffected, heterozygous variants in the GJB2 and SERPINB7 genes were detected in the parents, respectively, which are associated with deafness and palmoplantar keratoderma. Our research indicated that pES can provide significant critical information for families with morphologically normal fetuses. Prenatal screening with exome sequencing requires careful management and detailed pre-test and post-test genetic counseling.

Multicenter appraisal of comorbid TANGO2 deficiency disorder in patients with 22q11.2 deletion syndrome.

TANGO2 deficiency disorder (TDD) is a rare, autosomal recessive condition caused by pathogenic variants in TANGO2, a gene residing within the region commonly deleted in 22q11.2 deletion syndrome (22q11.2DS). Although patients with 22q11.2DS are at substantially higher risk for comorbid TDD, it remains underdiagnosed within 22q11.2DS, likely due to overlapping symptomatology and a lack of knowledge about TDD. Initiation of B-vitamin supplementation may provide therapeutic benefit in TDD, highlighting the need for effective screening methods to improve diagnosis rates in this at-risk group. In this retrospective, multicenter study, we evaluated two cohorts of patients with 22q11.2DS (total N = 435) for possible comorbid TDD using two different symptom-based screening methods (free text-mining and manual chart review versus manual chart review alone). The methodology of the cohort 1 screening method successfully identified a known 22q11.2DS patient with TDD. Combined, these two cohorts identified 21 living patients meeting the consensus recommendation for TANGO2 testing for suspected comorbid TDD. Of the nine patients undergoing TANGO2 sequencing with del/dup analysis, none were ultimately diagnosed with TDD. Of the 12 deaths in the suspected comorbid TDD cohort, some of these patients exhibited symptoms (rhabdomyolysis, cardiac arrhythmia, or metabolic crisis) suspicious of comorbid TDD contributing to their death. Collectively, these findings highlight the need for robust prospective screening tools for diagnosing comorbid TDD in patients with 22q11.2DS.

Diagnostic Challenges in a Family with Dominant Dystrophic Epidermolysis Bullosa and Isolated Hereditary Nail Disorder: Paternal Gonosomal Mosaicism for COL7A1 Mutation and Maternal RSPO4 Variant.

Dystrophic epidermolysis bullosa (DEB) has long been recognized as a well-known genodermatosis, caused by COL7A1 gene pathogenic variants. Isolated anonychia associated with RSPO4 gene mutation is a recently described non-syndromic autosomal recessive condition. In this family, a 13-year-old girl presented with severe epidermolysis bullosa symptoms. Family history revealed milder but similar complaints in the siblings, and anonychia affecting all nails in the mother and maternal relatives. The father did not have any signs of DEB. Genetic testing revealed heterozygous c.6127G>A (p.Gly2043Arg) variant in the COL7A1 (NM_000094.4) gene, in the proband and her affected siblings. The variant was not detected in the mother or father, prompting investigation into parental mosaicism. Detection of the variant in sperm sample suggested paternal mosaicism. Additionally, RSPO4 gene (NM_001029871.4) was sequenced in the mother and two of her affected sisters for suspected non-syndromic isolated anonychia, revealing homozygous c.79+1G>A variant. Isolated nail disease in the mother was initially thought to be the result of DDEB nails-only subtype and the DEB in the children was inherited from the mother. However, further clinical and genetic investigation showed that the condition in the patient and her siblings arose from gonosomal mosaicism in the father and the nail phenotype in the mother is a separate coincidental condition. This report aims to serve as an example for similar cases and highlight the importance of detailed genetic analysis guided by comprehensive medical history in reaching a diagnosis.

A Case Report on Wilson’s Disease

The accumulation of copper in the liver, brain, cornea, and kidneys is the hallmark of Wilson's disease, an uncommon autosomal recessive condition. There is no community-based research on the prevalence and incidence of Wilson's disease in India; this study is hospital-based. Overview of the Case: A 10-year-old girl with serious complaints of burning micturition, giddiness, loose stools and blood in stools, yellowish discolouration of skin and sclera, generalized body aches, fever and stomach pain with distension was brought to the paediatric department. Wilson's illness was established by abdominal USG using the increased levels of urine copper, whole blood picture, liver function tests, and serum electrolytes and decreased levels of ceruloplasmin. The prominent characteristic, which is less common in youngsters, is the Kayser Fleisher ring. It is identified by a discoloration of the corneal edge that is greenish-brown in colour and eventually goes away with treatment. Probiotics, an antibiotic, a hepatoprotective drug, and copper chelators (D-penicillamine and zinc) were used in her treatment. Gradually she showed improvement in clinical signs and LFT levels.

Unraveling DREAM-PL: A Case Report on Challenges and Management

An uncommon autosomal recessive condition called DREAM-PL syndrome is typified by dysmorphic facial features, renal agenesis, male ambiguous genitalia, microcephaly, polydactyly, and lissencephaly. The CTU2 gene, which is in charge of tRNA post-transcriptional modification, is mutated in the syndrome. This alteration is necessary for the correct translation of genes, and its disruption can result in several aberrant embryonic processes. The severity of DREAM-PL syndrome can vary from moderate to severe, and the clinical characteristics can be diverse. While some patients may exhibit only some of the distinguishing features, others may have all of them. The most common characteristics include ambiguous genitalia, dysmorphic facies, and microcephaly. Diagnosis of DREAM-PL syndrome is typically based on clinical signs and confirmed through genetic testing, which can identify mutations in the CTU2 gene. Material and methodology: In the case being referred to as a study, a 37-week-old male neonate was delivered by lower segment cesarean section. The baby's birth weight was 2.760 Kg, and a heterozygous CMP mutation of the CTU2 gene was confirmed through whole-exome sequencing (WES). Unfortunately, there is currently no known cure for DREAM-PL syndrome. Result: Treatment focuses on managing the symptoms and providing supportive care. In some cases, surgical correction of birth defects may be beneficial.