Myhre syndrome in adulthood: clinical variability and emerging genotype-phenotype correlations.

Myhre syndrome (MS, MIM 139210) is a rare multisystemic disorder caused by recurrent pathogenic missense variants in SMAD4. The clinical features have been mainly documented in childhood and comprise variable neurocognitive development, recognizable craniofacial features, a short stature with a pseudo-muscular build, hearing loss, thickened skin, joint limitations, diverse cardiovascular and airway manifestations, and increased fibrosis often following trauma or surgery. In contrast, adults with MS are underreported obscuring potential clinical variability.

Targeted Next-Generation Sequencing in Children With Bilateral Sensorineural Hearing Loss: Diagnostic Yield and Predictors of a Genetic Cause.

Objective: To investigate the diagnostic yield of targeted next-generation sequencing using hearing loss panels and to identify patient-related factors that are associated with a definite genetic cause.

Study Design: Retrospective chart review.

Setting: Tertiary referral center.

Multi-omics approach dissects cis-regulatory mechanisms underlying North Carolina macular dystrophy, a retinal enhanceropathy.

North Carolina macular dystrophy (NCMD) is a rare autosomal-dominant disease affecting macular development. The disease is caused by non-coding single-nucleotide variants (SNVs) in two hotspot regions near PRDM13 and by duplications in two distinct chromosomal loci, overlapping DNase I hypersensitive sites near either PRDM13 or IRX1. To unravel the mechanisms by which these variants cause disease, we first established a genome-wide multi-omics retinal database, RegRet.

Patients carrying the mutation p.R406W in MAPT present with non-conforming phenotypic spectrum.

The missense mutation p.R406W in microtubule-associated protein tau leads to frontotemporal lobar degeneration with an amnestic, Alzheimer's disease-like phenotype with an autosomal dominant pattern of inheritance. In 2003, we described the pedigree of a Belgian family, labelled ADG, with 28 p.

Prevalence of Germline Pathogenic Variants in Cancer Predisposing Genes in Czech and Belgian Pancreatic Cancer Patients.

(1) Background: The proportion and spectrum of germline pathogenic variants (PV) associated with an increased risk for pancreatic ductal adenocarcinoma (PDAC) varies among populations. (2) Methods: We analyzed 72 Belgian and 226 Czech PDAC patients by multigene panel testing. The prevalence of pathogenic variants (PV) in relation to personal/family cancer history were evaluated.

Etiological Work-up in Referrals From Neonatal Hearing Screening: 20 Years of Experience.

Background: Confirmation of permanent hearing loss in a newborn should be followed by a search for an underlying etiology because this may impact hearing loss management and counselling.

Methods: Retrospective chart review of all newborns seen at a tertiary referral center after referral from newborn hearing screening over a 20-year period. The changes in the diagnostic protocol over the years are outlined and the most recent protocol includes targeted next-generation sequencing using a panel for known hearing loss causing genes, in all cases of bilateral sensorineural hearing loss (SNHL).

Correction: Biallelic sequence and structural variants in RAX2 are a novel cause for autosomal recessive inherited retinal disease.

The original version of this Article contained an incorrect version of Fig. 3, which included two variants initially shown in black text in Fig. 3a that the authors removed from the final manuscript.

Biallelic sequence and structural variants in RAX2 are a novel cause for autosomal recessive inherited retinal disease.

Purpose: RAX2 encodes a homeobox-containing transcription factor, in which four monoallelic pathogenic variants have been described in autosomal dominant cone-dominated retinal disease.

Methods: Exome sequencing in a European cohort with inherited retinal disease (IRD) (n = 2086) was combined with protein structure modeling of RAX2 missense variants, bioinformatics analysis of deletion breakpoints, haplotyping of RAX2 variant c.335dup, and clinical assessment of biallelic RAX2-positive cases and carrier family members.

Molecular analysis of an asbestos-exposed Belgian family with a high prevalence of mesothelioma.

Familial clustering of malignant mesothelioma (MM) has been linked to the presence of germline mutations in BAP1. However, families with multiple MM patients, without segregating BAP1 mutation were described, suggesting the existence of other predisposing genetic factors. In this study, we report a previously undescribed Belgian family, in which BAP1 was found to be absent in the epithelial malignant mesothelial cells of the index patient.

Role of Targeted Next Generation Sequencing in the Etiological Work-Up of Congenitally Deaf Children.

Objectives: The purpose of this study is to report the results of a comprehensive etiological work-up for congenitally deaf children including targeted next generation sequencing.

Study Design: Retrospective case review.

Setting: Tertiary referral center.

Auditory neuropathy spectrum disorder (ANSD) in referrals from neonatal hearing screening at a well-baby clinic.

Unlabelled: Auditory neuropathy spectrum disorder (ANSD) is a particular kind of hearing disorder characterised by normal outer hair cell function and abnormal or absent auditory brain stem responses. Little data are available regarding the prevalence of this condition in healthy newborns. We performed a retrospective medical records review of 791 referrals from universal neonatal hearing screening (UNHS) at a well-baby clinic to investigate the prevalence of ANSD.

Increased chromosomal radiosensitivity in asymptomatic carriers of a heterozygous BRCA1 mutation.

Background: Breast cancer risk increases drastically in individuals carrying a germline BRCA1 mutation. The exposure to ionizing radiation for diagnostic or therapeutic purposes of BRCA1 mutation carriers is counterintuitive, since BRCA1 is active in the DNA damage response pathway. The aim of this study was to investigate whether healthy BRCA1 mutations carriers demonstrate an increased radiosensitivity compared with healthy individuals.

DNA Diagnostics of Hereditary Hearing Loss: A Targeted Resequencing Approach Combined with a Mutation Classification System.

Although there are nearly 100 different causative genes identified for nonsyndromic hearing loss (NSHL), Sanger sequencing-based DNA diagnostics usually only analyses three, namely, GJB2, SLC26A4, and OTOF. As this is seen as inadequate, there is a need for high-throughput diagnostic methods to detect disease-causing variations, including single-nucleotide variations (SNVs), insertions/deletions (Indels), and copy-number variations (CNVs). In this study, a targeted resequencing panel for hearing loss was developed including 79 genes for NSHL and selected forms of syndromic hearing loss.

Further delineation of facioaudiosymphalangism syndrome: Description of a family with a novel NOG mutation and without hearing loss.

Mutations in the NOG gene give rise to a wide range of clinical phenotypes. Noggin, the protein encoded by this gene is a secreted modulator of multiple pathways involved in both bone and joint development. Proximal symphalangism is commonly observed in patients bearing mutations in this gene, however secondary symptomes are often found including typical facies with hemicylindrical nose with bulbous tip, hyperopia, reduced mobility of multiple joints, hearing loss due to stapes fixation, and recurrent pain from affected joints.

Phenotype and genotype in 103 patients with tricho-rhino-phalangeal syndrome.

Tricho-rhino-phalangeal syndrome (TRPS) is characterized by craniofacial and skeletal abnormalities, and subdivided in TRPS I, caused by mutations in TRPS1, and TRPS II, caused by a contiguous gene deletion affecting (amongst others) TRPS1 and EXT1. We performed a collaborative international study to delineate phenotype, natural history, variability, and genotype-phenotype correlations in more detail. We gathered information on 103 cytogenetically or molecularly confirmed affected individuals.

A study of the clinical and radiological features in a cohort of 93 patients with a COL2A1 mutation causing spondyloepiphyseal dysplasia congenita or a related phenotype.

Type 2 collagen disorders encompass a diverse group of skeletal dysplasias that are commonly associated with orthopedic, ocular, and hearing problems. However, the frequency of many clinical features has never been determined. We retrospectively investigated the clinical, radiological, and genotypic data in a group of 93 patients with molecularly confirmed SEDC or a related disorder.

Further delineation of the KAT6B molecular and phenotypic spectrum.

KAT6B sequence variants have been identified previously in both patients with the Say-Barber-Biesecker type of blepharophimosis mental retardation syndromes (SBBS) and in the more severe genitopatellar syndrome (GPS). We report on the findings in a previously unreported group of 57 individuals with suggestive features of SBBS or GPS. Likely causative variants have been identified in 34/57 patients and were commonly located in the terminal exons of KAT6B.

The transcriptional regulator ADNP links the BAF (SWI/SNF) complexes with autism.

Mutations in ADNP were recently identified as a frequent cause of syndromic autism, characterized by deficits in social communication and interaction and restricted, repetitive behavioral patterns. Based on its functional domains, ADNP is a presumed transcription factor. The gene interacts closely with the SWI/SNF complex by direct and experimentally verified binding of its C-terminus to three of its core components.

A SWI/SNF-related autism syndrome caused by de novo mutations in ADNP.

Despite the high heritability of autism spectrum disorders (ASD), characterized by persistent deficits in social communication and interaction and restricted, repetitive patterns of behavior, interests or activities, a genetic diagnosis can be established in only a minority of patients. Known genetic causes include chromosomal aberrations, such as the duplication of the 15q11-13 region, and monogenic causes, as in Rett and fragile-X syndromes. The genetic heterogeneity within ASD is striking, with even the most frequent causes responsible for only 1% of cases at the most.

Myhre and LAPS syndromes: clinical and molecular review of 32 patients.

Myhre syndrome is characterized by short stature, brachydactyly, facial features, pseudomuscular hypertrophy, joint limitation and hearing loss. We identified SMAD4 mutations as the cause of Myhre syndrome. SMAD4 mutations have also been identified in laryngotracheal stenosis, arthropathy, prognathism and short stature syndrome (LAPS).

The genetic basis of DOORS syndrome: an exome-sequencing study.

Background: Deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS) syndrome is a rare autosomal recessive disorder of unknown cause. We aimed to identify the genetic basis of this syndrome by sequencing most coding exons in affected individuals.

Methods: Through a search of available case studies and communication with collaborators, we identified families that included at least one individual with at least three of the five main features of the DOORS syndrome: deafness, onychodystrophy, osteodystrophy, intellectual disability, and seizures.

Phenotypic spectrum of Simpson-Golabi-Behmel syndrome in a series of 42 cases with a mutation in GPC3 and review of the literature.

Simpson-Golabi-Behmel syndrome (SGBS) is a rare X-linked multiple congenital abnormality/intellectual disability syndrome characterized by pre- and post-natal overgrowth, distinctive craniofacial features, macrocephaly, variable congenital malformations, organomegaly, increased risk of tumor and mild/moderate intellectual deficiency. In 1996, Glypican 3 (GPC3) was identified as the major gene causing SGBS but the mutation detection rate was only 28-70%, suggesting either genetic heterogeneity or that some patients could have alternative diagnoses. This was particularly suggested by some reports of atypical cases with more severe prognoses.