Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) due to polyAla site variant in diagnostic challenges with NGS.

This report presents a case of blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) identified in a term neonate. This patient presented with the four typical ophthalmic signs: short horizontal palpebral fissures (blepharophimosis), impaired levator palpebrae superioris muscle function leading to drooping of upper eyelids (ptosis), skin folding on the medial lower eyelid ascending to the upper eyelid (epicanthus inversus) and increased medial intercanthal distance (telecanthus). On genetic analysis, a polyalanine (polyAla) tract expansion in the gene was identified.

Deep phenotyping of patients with citrin deficiency in Singapore- single centre experience.

Background: Citrin deficiency (CD) is a pan-ethnic autosomal recessive inborn error of metabolism due to-pathogenic variants in the SLC25A13 gene which results in disruptions of multiple metabolic pathways including glycolysis, gluconeogenesis, lipogenesis, the urea cycle, and tricarboxylic cycle.

Methods: A retrospective observational study of CD patients managed according to standard clinical practice at a single centre in Singapore (KK Women's and Children's Hospital, KKH) was undertaken from August 2016-August 2024. We present the largest cohort of patients reported in Southeast Asia focusing on clinical, biochemical and imaging findings at diagnosis, and long-term outcomes/management (including drug therapy, food preferences/adherence, hospital admissions, growth, neurodevelopmental, biochemical, and imaging outcomes).

Undiagnosed Hackathon Ends Diagnostic Odyssey in a Patient With DNA2-Related Rothmund-Thomson Syndrome.

Rothmund-Thomson syndrome (RTS) is an ultra-rare, genetically heterogeneous autosomal recessive genodermatosis characterized by poikiloderma, sparse hair and eyebrows, photosensitivity, and short stature. The recently described RTS type 4 (RTS-4), caused by biallelic variants in the DNA2 gene, is associated with additional distinctive features such as microphthalmia, corneal opacity, congenital cataracts (rather than juvenile), and hypothyroidism. To date, eight individuals with RTS-4 have been reported, all carrying a deep intronic variant in DNA2 (ENST00000358410.

Cardiofaciocutaneous syndrome and immunodeficiency: data from an international multicenter cohort.

Introduction: Cardiofaciocutaneous syndrome (CFCS) is a rare syndromic disorder caused by germline mutations affecting the RAS/MAPK pathway. It is characterized by distinctive craniofacial dysmorphism, congenital heart defects, skin abnormalities, gastrointestinal dysfunction, neurocognitive impairment, and epilepsy. Emerging evidence suggests an association with hypogammaglobulinemia, but a comprehensive characterization of immunological abnormalities in CFCS is lacking.

The ClinGen Syndromic Disorders Gene Curation Expert Panel: Assessing the clinical validity of 111 gene-disease relationships.

Purpose: The Clinical Genome Resource (ClinGen) Gene Curation Expert Panels have historically focused on specific organ systems or phenotypes; thus, the ClinGen Syndromic Disorders Gene Curation Expert Panel (SD-GCEP) was formed to address an unmet need.

Methods: The SD-GCEP applied ClinGen's framework to evaluate the clinical validity of genes associated with rare syndromic disorders. A total of 111 gene-disease relationships (GDRs) associated with 100 genes spanning the clinical spectrum of syndromic disorders were curated.

A Novel Frameshift Variant Causes GATAD2B-Associated Neurodevelopmental Disorder with Camptodactyly.

Introduction: GATAD2B-associated neurodevelopmental disorder (GAND) is caused by pathogenic variants in which encodes p66beta, a subunit of a transcription repressor. The main presentations of GAND are intellectual disability, speech impairment, and dysmorphism. However, these features overlap with other neurodevelopmental syndromes and are not specific enough to be recognised for a particular clinical diagnosis without molecular confirmation.

Premature ovarian insufficiency: When ovaries retire early.

Introduction: Premature ovarian insufficiency (POI) refers to loss of ovarian activity before the age 40 years. POI has significant detrimental effects on health (infertility, cardiovascular diseases, type 2 diabetes, reduced bone density, dementia), well-being and longevity. This summary is a practical toolkit for health-care professionals (HCPs) looking after women with POI.

Clinical Implementation of Nephrologist-Led Genomic Testing for Glomerular Diseases in Singapore: Rationale and Protocol.

Introduction: The early diagnosis and appropriate treatment of monogenic glomerular diseases can reduce kidney failure, avoid unnecessary investigations such as kidney biopsies and ineffective treatment with immunosuppressants, guide transplant decisions, and inform the genetic risks of their family members. Yet, genetic testing for kidney disease is underutilized in Singapore. We aimed to implement a nephrologist-led genetic service and evaluate the acceptance, adoption, utility, and cost-effectiveness of genetic testing for monogenic glomerular disease in Singapore.

The ClinGen Syndromic Disorders Gene Curation Expert Panel: Assessing the Clinical Validity of 111 Gene-Disease Relationships.

Purpose: The Clinical Genome Resource (ClinGen) Gene Curation Expert Panels (GCEPs) have historically focused on specific organ systems or phenotypes; thus, the ClinGen Syndromic Disorders GCEP (SD-GCEP) was formed to address an unmet need.

Methods: The SD-GCEP applied ClinGen's framework to evaluate the clinical validity of genes associated with rare syndromic disorders. 111 Gene-Disease Relationships (GDRs) associated with 100 genes spanning the clinical spectrum of syndromic disorders were curated.

Dilated aorta in CNOT3 -related neurodevelopmental disorder: 'expanding' the phenotype.

Introduction: Neurodevelopmental disorders (NDDs) comprise conditions that emerge during the child's development and contribute significantly to global health and economic burdens. De novo variants in CNOT3 have been linked to NDDs and understanding the genotype-phenotype relationship between CNOT3 and NDDs will aid in improving diagnosis and management.

Methods: In this study, we report a case of a patient with CNOT3 -related NDD who presented with progressive aortic dilatation, a feature not reported previously.

Cluster analysis and visualisation of electronic health records data to identify undiagnosed patients with rare genetic diseases.

Rare genetic diseases affect 5-8% of the population but are often undiagnosed or misdiagnosed. Electronic health records (EHR) contain large amounts of data, which provide opportunities for analysing and mining. Data mining, in the form of cluster analysis and visualisation, was performed on a database containing deidentified health records of 1.

To B(enign) or Not to B: functionalisation of variant in a mild form of argininosuccinate lyase deficiency identified through newborn screening.

Argininosuccinate lyase (ASL) deficiency is an autosomal recessive disorder of the urea cycle with a diverse spectrum of clinical presentation that is detectable in newborn screening. We report an 8-year-old girl with ASL deficiency who was detected through newborn screening and was confirmed using biochemical and functional assay. She is compound heterozygous for a likely pathogenic variant NM_000048.

The IFITM5 Ser40Leu variant can manifest as prenatal Caffey disease.

We report on a female neonate with a clinico-radiological presentation in keeping with a lethal form of prenatal Caffey disease (PCH). She had antenatal and postnatal features of severely bowed long bones, small chest, diaphyseal hyperostosis and polyhydramnios and died shortly after birth. Initial testing excluded COL1A1-related PCH, as an OI gene panel, consisting of COL1A1, COL1A2, CRTAP, and P3H1 genes, was negative.

Monozygotic twins with identical premature timing of acne onset: A Case report.

Acne vulgaris, a common dermatological condition that affects most adolescents and young adults, can indicate an underlying pathology if present prematurely in mid-childhood. Premature acne can be caused by premature adrenarche secondary to non-classical congenital adrenal hyperplasia (NC-CAH), a condition arising from 21-hydroxylase deficiency. This report describes a pair of monozygotic twin brothers with identical premature onset of acne, who were found to have an identical homozygous mutation in the promoter region of the CYP21A2 gene.

DEGS1 -related leukodystrophy: a clinical report and review of literature.

Background: Leukodystrophies are a heterogeneous group of disorders affecting the white matter of the central nervous system, with or without affecting the peripheral nervous system. Biallelic variants in DEGS1 , coding for desaturase 1 (Des1) protein, were recently reported to be associated with hypomyelinating leukodystrophy (HLD), a subclass of leukodystrophies where the formation of the myelin sheath is affected.

Methods: Genomic sequencing was performed on our index patient with severe developmental delay, severe failure to thrive, dystonia, seizures, and hypomyelination on brain imaging.

Reduced resource utilization with early use of next-generation sequencing in rare genetic diseases in an Asian cohort.

Children with genetic diseases endure a prolonged and costly "diagnostic odyssey." The use of whole exome sequencing (WES) and whole genome sequencing (WGS) has improved the diagnosis rate, ending the odyssey. However, the additional costs associated WES/WGS has impeded their adoption in Asian settings.

Fibrous dysplasia in cardio-facio-cutaneous syndrome: A case report and review of literature.

Cardio-facio-cutaneous (CFC) syndrome (OMIM #:115150, 615278, 615279, 615280) is a rare genetic condition caused by variants in the RAS/mitogen-activated protein kinase (MAPK) signal transduction pathway. Up to 75% of cases are caused by mutations in the BRAF gene, whereas KRAS gene mutation has only been reported in <2% of cases. CFC syndrome is characterized by cardiac abnormalities, distinctive craniofacial dysmorphism, and various cutaneous abnormalities.

Novel Variants and Clinical Characteristics of 16 Patients from Southeast Asia with Genetic Variants in Neurofibromin-1.

Neurofibromatosis type 1 (NF1) is one of the most common inherited disorders. It is caused by mutations in the neurofibromin-1 gene ( ) and affects the formation and growth of nerve tissues. More than 3,600 pathogenic variants in the gene have been identified from patients with most of the germline variants are from the Western populations.