Familial 3M Syndrome – as an Example of Diagnostic Difficulties in Rare Genetic Syndromes

Magdalena Pasińska,1 Joanna M Rusecka,2 Agnieszka Sobczyńska-Tomaszewska,2 Maciej Pasiński3 1Faculty of Medicine, Department of Clinical Genetics, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Bydgoszcz, Poland; 2Medical Center Medgen, Warsaw, Poland; 3Department of Orthopedics and Traumatology of the Locomotor System, Antoni Jurasz University Hospital No. 1, Bydgoszcz, PolandCorrespondence: Magdalena Pasińska, Department of Clinical Genetics, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Skłodowskiej - Curie 9, Bydgoszcz, 85-094, Poland, Tel/Fax +52 585 35 68, Email [email protected]; [email protected]: A lack of experience diagnosing and treating rare diseases contributes to delayed or incorrect diagnoses, and optimal clinical treatment is often unachievable. Miller-McKusick-Malvaux syndrome (3M syndrome, also known as dolichospondylic dysplasia) is a rare genetic disorder with unknown prevalence. It is inherited in an autosomal recessive manner and is characterized by severe intrauterine and postnatal growth retardation, dysmorphic facial features, and skeletal abnormalities.Methods: Whole exome sequencing (WES) was performed on the proband using Twist Human Core Exome Plus Kit (Twist Bioscience) and sequenced with Illumina technology (100x depth of mean coverage). Alignment and variant calling were performed with an in-house bioinformatics pipeline. The identified variants were annotated using the Ensembl VEP and multiple databases, including ClinVar, dbSNP, HGMD, and GnomAD. XHMMv1.0.Results: This article presents the diagnostic process in siblings diagnosed with 3M syndrome, caused by homozygous variant c.3523C > T (p.His1175Tyr) in the CUL7 gene.Discussion: This is the first description of a familial syndrome from a local population. Identifying new gene variants has helped expand the spectrum of variations associated with the pathogenesis of 3M syndrome. The expanding database of genetic variants, combined with knowledge of the spectrum and severity of a patient’s clinical symptoms, provides the opportunity to identify genotype-phenotype correlation relevant to medical care.Keywords: 3M syndrome, skeletal dysplasia, rare diseases, CUL7 gene, short stature