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ABSTRACT Shprintzen‐Goldberg‐syndrome (SGS) is caused by pathogenic exon 1 variants of SKI. Symptoms include dysmorphic features, skeletal and cardiovascular comorbidities, and cognitive and developmental impairments. We delineated the neurodevelopmental and behavioral features of SGS, as they are not well‐documented. We collected physician‐reported data of people with molecularly confirmed SGS through an international collaboration. We identified and deep‐phenotyped the neurodevelopmental and behavioral features in four patients. Within our cohort, all exhibited developmental delays in motor skills and/or speech, with the average age of first words at 2 years and 6 months and independent walking at 3 years and 5 months. All four had learning disabilities and difficulties regulating emotions and behavior. Intellectual disability, ranging from borderline to moderate, was present in all four participants. Moreover, we reviewed the literature and identified 52 additional people with SGS, and summarized the features across both datasets. Mean age was 23 years (9–48 years). When combining our cohort and reported cases, we found that 80% (45/56) had developmental and/or cognitive impairment, with the remainder having normal intelligence. Our study elucidates the developmental, cognitive, and behavioral features in participants with SGS and contributes to a better understanding of this rare condition. [ABSTRACT FROM AUTHOR]

The Division of Human Genetics (National Health Laboratory Service and University of the Witwatersrand) recently hosted the second annual Achondroplasia Day in Johannesburg. Participation in the meeting increased from 4 families in 2011 to 17 families in 2012. The main aim of the meeting was to bring individuals with achondroplasia and their families together and to facilitate improved interaction between families and the healthcare professionals involved in their care. This short report briefly describes the events of the day, and the immense benefit such activities have for families with rare genetic conditions. Additionally, we provide an overview of the basic genetics of achondroplasia and specific health needs of affected individuals. It is hoped that other centres around South Africa will be inspired to organise similar events in their respective areas to benefit their patients. [ABSTRACT FROM AUTHOR]

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., Results: From April 2020 through March 2024, 38 precurations were performed on genes with multiple disease relationships and were reviewed to determine if the disorders were part of a spectrum or distinct entities. 14 genes were lumped into a single disease entity and 24 were split into separate entities, of which 11 were curated by the SD-GCEP. A full review of 111 GDRs for 100 genes followed, with 78 classified as Definitive, 9 as Strong, 15 as Moderate, and 9 as Limited highlighting where further data are needed. All diseases involved two or more organ systems, while the majority (88/111 GDRs, 79.2%) had five or more organ systems affected., Conclusion: The SD-GCEP addresses a critical gap in gene curation efforts, enabling inclusion of genes for syndromic disorders in clinical testing and contributing to keeping pace with the rapid discovery of new genetic syndromes., Competing Interests: Conflict of Interest K.B., M.P.B., B.T.B., N.J.B., An.C., Ad.C., A.R.C, K.L.G., A.K., A.M., R.R., Z.Sc., J.P.T., A.J.C. are current or former employees and shareholders of Illumina Inc. K.B., J.M.H., D.L.T., B.W. are employees of Ambry Genetics. K.L.G. is an employee of Rady Children’s Institute for Genomic Medicine. SSJ is the co-founder of Global Gene Corporation Pte Ltd. J.P.T is an employee of Blueprint Genetics (a Quest company). AODL was a paid consultant for Tome Biosciences, Ono Pharma USA, and Addition Therapeutics and receives research funding from Pacific Biosciences. All other authors declare no conflicts of interest.

The most important factor that complicates the work of dysmorphologists is the significant phenotypic variability of the human face. Next-Generation Phenotyping (NGP) tools that assist clinicians with recognizing characteristic syndromic patterns are particularly challenged when confronted with patients from populations different from their training data. To that end, we systematically analyzed the impact of genetic ancestry on facial dysmorphism. For that purpose, we established the GestaltMatcher Database (GMDB) as a reference dataset for medical images of patients with rare genetic disorders from around the world. We collected 10,980 frontal facial images - more than a quarter previously unpublished - from 8,346 patients, representing 581 rare disorders. Although the predominant ancestry is still European (67%), data from underrepresented populations have been increased considerably via global collaborations (19% Asian and 7% African). This includes previously unpublished reports for more than 40% of the African patients. The NGP analysis on this diverse dataset revealed characteristic performance differences depending on the composition of training and test sets corresponding to genetic relatedness. For clinical use of NGP, incorporating non-European patients resulted in a profound enhancement of GestaltMatcher performance. The top-5 accuracy rate increased by +11.29%. Importantly, this improvement in delineating the correct disorder from a facial portrait was achieved without decreasing the performance on European patients. By design, GMDB complies with the FAIR principles by rendering the curated medical data findable, accessible, interoperable, and reusable. This means GMDB can also serve as data for training and benchmarking. In summary, our study on facial dysmorphism on a global sample revealed a considerable cross ancestral phenotypic variability confounding NGP that should be counteracted by international efforts for increasing data diversity. GMDB will serve as a vital reference database for clinicians and a transparent training set for advancing NGP technology.

Sirenomelia, also known as the 'mermaid malformation/syndrome', is a rare, serious congenital anomaly characterized by variable degrees of fusion of the lower limbs and associated severe malformations of the lower vertebral and genitourinary systems. In this report, we describe a series of African patients with sirenomelia. We present the clinical and radiological features of four black South African patients and illustrate some of the rarer associated abnormalities, which include asymmetrical upper limb defects, not confined to the radial ray. The clinical phenotypic overlap between caudal dysgenesis, VACTERL association and sirenomelia in our patients is highlighted, lending support to the theory that these entities may be different manifestations of a single pathogenic process.