A NOVEL DISEASE-CAUSING NF1 VARIANT IN A CROATIAN FAMILY WITH NEUROFIBROMATOSIS TYPE 1

Neurofibromatosis type 1 (NF1) is the most common autosomal dominant neurocutaneous syndrome with the estimated prevalence ranging from 1 in 3000 to 1 in 4000 individuals and wide phenotypical variability. NF1 is caused by autosomal dominant heterozygous mutations in the neurofibromin gene which is located on the chromosome 17 (17q11.2). Phenotypically, NF1 patients have a very heterogeneous clinical phenotype. In this study, a novel frameshift NF1 variant was identified in a Croatian family with NF1 (mother and two daughters). The novel variant c. 4482_4483delTA leads to sequence change that creates a premature translational stop signal (p.His1494Glnfs*7) in the NF1 gene. Our study showed that even when the same germline NF1 variant has been identified, there is still huge phenotypic variability in patients even within the same family, and it makes prognosis of the disease more complex. The development of next-generation sequencing technologies which allow rapid and accurate identification of disease-causing mutations becomes crucial for molecular characterization of NF1 patients as well as for patient follow-up, in the context of genetic counseling and clinical management of patients

A NOVEL DISEASE-CAUSING NF1 VARIANT IN A CROATIAN FAMILY WITH NEUROFIBROMATOSIS TYPE 1

Neurofibromatosis type 1 (NF1) is the most common autosomal dominant neurocutaneous syndrome with the estimated prevalence ranging from 1 in 3000 to 1 in 4000 individuals and wide phenotypical variability. NF1 is caused by autosomal dominant heterozygous mutations in the neurofibromin gene which is located on the chromosome 17 (17q11.2). Phenotypically, NF1 patients have a very heterogeneous clinical phenotype. In this study, a novel frameshift NF1 variant was identified in a Croatian family with NF1 (mother and two daughters). The novel variant c. 4482_4483delTA leads to sequence change that creates a premature translational stop signal (p.His1494Glnfs*7) in the NF1 gene. Our study showed that even when the same germline NF1 variant has been identified, there is still huge phenotypic variability in patients even within the same family, and it makes prognosis of the disease more complex. The development of next-generation sequencing technologies which allow rapid and accurate identification of disease-causing mutations becomes crucial for molecular characterization of NF1 patients as well as for patient follow-up, in the context of genetic counseling and clinical management of patients

Genotype-phenotype correlation in contactin-associated protein-like 2 (<i>CNTNAP-2</i>) developmental disorder

Open access funding provided by Università degli Studi di Genova within the CRUI-CARE Agreement. SS receives funding from the National Institutes of Health National Institute of Neurological Disorders and Stroke (K23NS119666). VN is supported by the Ludwig Boltzmann Gesellschaft core funding, the Austrian Science Fund (FWF): P 32924 and TAI 202 1000 Ideas Project.Contactin-associated protein-like 2 (CNTNAP2) gene encodes for CASPR2, a presynaptic type 1 transmembrane protein, involved in cell–cell adhesion and synaptic interactions. Biallelic CNTNAP2 loss has been associated with “Pitt-Hopkins-like syndrome-1” (MIM#610042), while the pathogenic role of heterozygous variants remains controversial. We report 22 novel patients harboring mono- (n = 2) and bi-allelic (n = 20) CNTNAP2 variants and carried out a literature review to characterize the genotype–phenotype correlation. Patients (M:F 14:8) were aged between 3 and 19 years and affected by global developmental delay (GDD) (n = 21), moderate to profound intellectual disability (n = 17) and epilepsy (n = 21). Seizures mainly started in the first two years of life (median 22.5 months). Antiseizure medications were successful in controlling the seizures in about two-thirds of the patients. Autism spectrum disorder (ASD) and/or other neuropsychiatric comorbidities were present in nine patients (40.9%). Nonspecific midline brain anomalies were noted in most patients while focal signal abnormalities in the temporal lobes were noted in three subjects. Genotype–phenotype correlation was performed by also including 50 previously published patients (15 mono- and 35 bi-allelic variants). Overall, GDD (p Publisher PDFPeer reviewe