Speaker
Description
Background: Cranial sutures are essential developmental structures that separate the cranial bones to enable the bones to grow to accommodate the developing brain. The metopic, bi-coronal, sagittal and lambdoid sutures must remain patent at different time points in post-natal development, with premature fusion of these sutures leading to craniosynostosis. Craniosynostosis may negatively impact brain development, leading to many neurodevelopmental anomalies. According to OMIM, >180 genetic syndromes present with craniosynostosis. Arrhinia is the congenital absence or underdevelopment of the nose, often affecting breathing and feeding. This study deciphered the genetic aetiology of two extremely rare cases of craniosynostosis presenting with arrhinia, cleft palate and other developmental anomalies.
Methods: Whole exome sequencing (WES) was undertaken on DNA obtained from the proband, utilising Illumina HiSeq at 100X and GRCh38. Quality control, read alignment and variant calling were carried out using Sentieon 202112.01 pipeline. Normalised VCF files were annotated using Ensembl VEP. Variants with MAF >0.01 were filtered out, and the pathogenicity of variants was determined using 12 tools embedded in dbNSFP, ClinVar and other tools like SpliceAI. Pathogenic variants were prioritised based on American College of Medical Genetics and Genomics (ACMG) guidelines and VarElect.
Results: A novel heterozygous stop-gain (c.4493G>A, p.Trp1498Ter) and missense (c.929G>A, p.Arg310Gln) mutations were observed in TRPM3, a gene associated with autosomal dominant Neurodevelopmental Disorder with Hypotonia, Dysmorphic Facies, and Skeletal Anomalies, with or without Seizures (NEDFSS; OMIM:620224). Other co-occurring variants that may lead to autosomal dominant genetic syndromes that could explain other anomalies in one proband included RFX7 (c.2801T>G;p.Phe934Cys), SH3BP4 (c.1837C>G;p.Pro613Ala), LHX4 (c.1147G>C;p.Asp383His) and PAX6 (c.2041G>A;p.Gly681Arg).
Conclusions: The probands are most likely to have NEDFSS, as the phenotypes of this syndrome match those of the probands. The novel TRPM3 variant highlights the importance of including diverse populations in genetic studies to inform diagnostics, genetic counselling, and targeted molecular therapeutics.