Biomedical subjects

Henrike Lisa Sczakiel

Publications and source records attributed to Henrike Lisa Sczakiel.

3 recordsLinked to original sources

PubMed2026

Long-read sequencing reveals a hidden Alu-mediated splice defect in CPLANE1, causing orofaciodigital syndrome type VI.

Orofaciodigital syndrome type VI (OFD VI) is a recessive ciliopathy characterized by excessive polydactyly, molar tooth sign, cleft lip, and developmental delay, caused by pathogenic variants in CPLANE1. Here, we present a patient with OFD VI that remained genetically unexplained after routine genetic testing, including short-read whole genome sequencing (WGS). Using long-read sequencing, we found two biallelic splice-site variants in CPLANE1, c.8633-4_8633-3del, and an Alu element insertion close to an exon-intron boundary. Transcript analysis showed that each variant independently resulted in exon skipping, and quantitative expression studies revealed reduced total CPLANE1 mRNA levels in patient-derived fibroblasts. Based on these findings, we were able to re-classify the c.8633-4_8633-3del variant from a variant of uncertain significance (VUS) to likely pathogenic. The identification of an Alu element insertion missed by short-read WGS highlights the added diagnostic value of long-read sequencing in uncovering cryptic, transposable element-associated pathogenic variants.

Journal Article↗

PubMed2026

Identification of biallelic loss-of-function PREP variants in three individuals with syndromic intellectual disability.

BACKGROUND: Neurodevelopmental disorders are one of the most prevalent reasons for genetic testing in childhood. Despite the identification of over 1950 associated genes, many proposed candidate genes lack convincing gene-disease validity. The gene PREP encodes the broadly expressed prolyl endopeptidase whose exact function remains largely unknown. A homozygous PREP variant has been reported once as a candidate gene in two siblings with intellectual disability but no functional studies were conducted. METHODS: Exome and trio genome sequencing were performed in two unrelated families as part of larger cohorts. Segregation analysis, RNA sequencing and immunoblots were performed to further examine the pathogenicity of detected PREP variants. RESULTS: We report three individuals from two unrelated families who presented with intellectual disability, behavioural abnormalities, strabismus, generalised muscular hypotonia, dysmorphic facial features and epilepsy. Exome and genome sequencing identified two different homozygous rare PREP variants: c.1570_1573dup, p.(Asn525Thrfs*5) and c.1839-2A>G, p.?. RNA sequencing confirmed the detected intronic variant to result in two aberrant mRNA isoforms. In patient-derived cells immunoblots showed absence of PREP protein. CONCLUSION: Our data suggest PREP deficiency as the underlying cause of a syndromic neurodevelopmental disorder.

Female↗

PubMed2026

Variants leading to ELAVL2 haploinsufficiency cause a neurodevelopmental disorder with prominent cognitive, behavioral, and neurological features.

RNA-binding proteins (RBPs) regulate gene expression, and a number of RBPs have been implicated in brain function and behavior. Here, we report 16 individuals with a neurodevelopmental disorder and de novo heterozygous variants in ELAVL2, encoding an RBP not previously linked to Mendelian disease. Thirteen individuals were identified through GeneMatcher. Their ELAVL2 variants include two structural, five nonsense, and six missense variants, supporting haploinsufficiency as the primary disease mechanism. The cohort presented with developmental delay, intellectual disability, autism spectrum disorder, seizures, sleep problems, sensory processing issues, emotional instability, and difficulty with socialization. Three additional variants (two missense and one terminal exon truncation), each previously reported in a different large cohort study, were also included for follow-up investigations. We provide multiple lines of evidence linking variants in ELAVL2 to the observed neurodevelopmental and behavioral phenotypes. First, we show that common genetic variants in ELAVL2 are significantly associated with intelligence, motor development, sleep-related traits, and sociability in the general population. Drosophila loss-of-function models provide further independent evidence for a conserved role in the regulation of seizure-like behavior, sensory processing, and sleep. Molecular studies confirm that some of the missense variants are deleterious, leading to decreased protein levels. Together, our integrative study combining Mendelian genetics, clinical and association studies, and animal and molecular modeling supports variants in ELAVL2 as a cause of a neurodevelopmental disorder, with haploinsufficiency as the disease mechanism, and identifies crucial roles of ELAVL2 in neuronal function, cognition, and behavior.

Humans↗