Presenting Clinical Information on Rare Chromosome 6 Disorders via a Parent-Centered Website: Parental and Professional Views.

The scarcity of clinical information surrounding rare chromosome disorders poses challenges for parents and clinicians. To bridge this gap for chromosome 6 disorders, the Chromosome 6 Project collects detailed genotype and phenotype data, aiming to provide aberration-specific phenotype information to parents via an interactive website. With input from 32 parents and 21 professionals, including medical doctors, cytogeneticists, health psychologists, and communication specialists, we used a three-round Delphi method to determine the type and amount of health-related information to be presented on this website.

Consensus recommendations on counselling in Phelan-McDermid syndrome, with special attention to recurrence risk and to ring chromosome 22.

This paper focuses on genetic counselling in Phelan-McDermid syndrome (PMS), a rare neurodevelopmental disorder caused by a deletion 22q13.3 or a pathogenic variant in SHANK3. It is one of a series of papers written by the European PMS consortium as a consensus guideline.

Definition and clinical variability of SHANK3-related Phelan-McDermid syndrome.

Phelan-McDermid syndrome (PMS) is an infrequently described syndrome that presents with a disturbed development, neurological and psychiatric characteristics, and sometimes other comorbidities. As part of the development of European medical guidelines we studied the definition, phenotype, genotype-phenotype characteristics, and natural history of the syndrome. The number of confirmed diagnoses of PMS in different European countries was also assessed and it could be concluded that PMS is underdiagnosed.

The phenotypic spectrum of terminal and subterminal 6p deletions based on a social media-derived cohort and literature review.

Background: Terminal 6p deletions are rare, and information on their clinical consequences is scarce, which impedes optimal management and follow-up by clinicians. The parent-driven Chromosome 6 Project collaborates with families of affected children worldwide to better understand the clinical effects of chromosome 6 aberrations and to support clinical guidance. A microarray report is required for participation, and detailed phenotype information is collected directly from parents through a multilingual web-based questionnaire.

Parent-reported phenotype data on chromosome 6 aberrations collected via an online questionnaire: data consistency and data availability.

Background: Even with the introduction of new genetic techniques that enable accurate genomic characterization, knowledge about the phenotypic spectrum of rare chromosomal disorders is still limited, both in literature and existing databases. Yet this clinical information is of utmost importance for health professionals and the parents of children with rare diseases. Since existing databases are often hampered by the limited time and willingness of health professionals to input new data, we collected phenotype data directly from parents of children with a chromosome 6 disorder.

The phenotypic spectrum of terminal 6q deletions based on a large cohort derived from social media and literature: a prominent role for DLL1.

Background: Terminal 6q deletions are rare, and the number of well-defined published cases is limited. Since parents of children with these aberrations often search the internet and unite via international social media platforms, these dedicated platforms may hold valuable knowledge about additional cases. The Chromosome 6 Project is a collaboration between researchers and clinicians at the University Medical Center Groningen and members of a Chromosome 6 support group on Facebook.

Mechanism of Disease: Recessive ADAMTSL4 Mutations and Craniosynostosis with Ectopia Lentis.

Craniosynostosis, the premature fusion of the calvarial bones, has numerous etiologies. Among them, several involve mutations in genes related to the TGFb signaling pathway, a critical molecular mediator of human development. These TGFb pathway-associated craniosynostosis syndromes include Loeys-Dietz syndrome (LDS) and Shprintzen-Goldberg syndrome (SGS).

TAB2 deletions and variants cause a highly recognisable syndrome with mitral valve disease, cardiomyopathy, short stature and hypermobility.

Deletions that include the gene TAB2 and TAB2 loss-of-function variants have previously been associated with congenital heart defects and cardiomyopathy. However, other features, including short stature, facial dysmorphisms, connective tissue abnormalities and a variable degree of developmental delay, have only been mentioned occasionally in literature and thus far not linked to TAB2. In a large-scale, social media-based chromosome 6 study, we observed a shared phenotype in patients with a 6q25.

Approach to Diagnosing a Pediatric Patient With Severe Insulin Resistance in Low- or Middle-income Countries.

Diabetes mellitus (DM) in children is most often caused by impaired insulin secretion (type 1 DM). In some children, the underlying mechanism for DM is increased insulin resistance, which can have different underlying causes. While the majority of these children require insulin dosages less than 2.

CHARGE syndrome and related disorders: a mechanistic link.

CHARGE syndrome is an autosomal dominant malformation disorder caused by pathogenic variants in the chromatin remodeler CHD7. Affected are craniofacial structures, cranial nerves and multiple organ systems. Depending on the combination of malformations present, its distinction from other congenital disorders can be challenging.

EPHA7 haploinsufficiency is associated with a neurodevelopmental disorder.

Ephrin receptor and their ligands, the ephrins, are widely expressed in the developing brain. They are implicated in several developmental processes that are crucial for brain development. Deletions in genes encoding for members of the Eph/ephrin receptor family were reported in several neurodevelopmental disorders.

Changes in empowerment and anxiety of patients and parents during genetic counselling for epilepsy.

Genetic testing and counselling are increasingly important in epilepsy care, aiming at finding a diagnosis, understanding aetiology and improving treatment and outcome. The psychological impact of genetic counselling from patients' or parents' perspectives is, however, unknown. We studied the counselee-reported outcome of genetic counselling before and after genetic testing for epilepsy by evaluating empowerment - a key outcome goal of counselling reflecting cognitive, decisional and behavioural control, emotional regulation and hope - and anxiety.

Loss-of-function and missense variants in NSD2 cause decreased methylation activity and are associated with a distinct developmental phenotype.

Purpose: Despite a few recent reports of patients harboring truncating variants in NSD2, a gene considered critical for the Wolf-Hirschhorn syndrome (WHS) phenotype, the clinical spectrum associated with NSD2 pathogenic variants remains poorly understood.

Methods: We collected a comprehensive series of 18 unpublished patients carrying heterozygous missense, elongating, or truncating NSD2 variants; compared their clinical data to the typical WHS phenotype after pooling them with ten previously described patients; and assessed the underlying molecular mechanism by structural modeling and measuring methylation activity in vitro.

Results: The core NSD2-associated phenotype includes mostly mild developmental delay, prenatal-onset growth retardation, low body mass index, and characteristic facial features distinct from WHS.

Under-reported aspects of diagnosis and treatment addressed in the Dutch-Flemish guideline for comprehensive diagnostics in disorders/differences of sex development.

We present key points from the updated Dutch-Flemish guideline on comprehensive diagnostics in disorders/differences of sex development (DSD) that have not been widely addressed in the current (inter)national literature. These points are of interest to physicians working in DSD (expert) centres and to professionals who come across persons with a DSD but have no (or limited) experience in this area. The Dutch-Flemish guideline is based on internationally accepted principles.

An analysis of body proportions in children with CHARGE syndrome using photogrammetric anthropometry.

Background: Growth retardation is one of the main hallmarks of CHARGE syndrome (CS), yet little is known about the body proportions of these children. Knowledge of body proportions in CS may contribute to a better characterization of this syndrome. This knowledge is important when considering starting growth-stimulating therapy.

GRIN2A-related disorders: genotype and functional consequence predict phenotype.

Alterations of the N-methyl-d-aspartate receptor (NMDAR) subunit GluN2A, encoded by GRIN2A, have been associated with a spectrum of neurodevelopmental disorders with prominent speech-related features, and epilepsy. We performed a comprehensive assessment of phenotypes with a standardized questionnaire in 92 previously unreported individuals with GRIN2A-related disorders. Applying the criteria of the American College of Medical Genetics and Genomics to all published variants yielded 156 additional cases with pathogenic or likely pathogenic variants in GRIN2A, resulting in a total of 248 individuals.

encephalopathy: A distinctive generalized developmental and epileptic encephalopathy.

Objective: To delineate the epileptology, a key part of the phenotypic spectrum, in a large patient cohort.

Methods: Patients were recruited via investigators' practices or social media. We included patients with (likely) pathogenic variants or chromosome 6p21.

PRRT2-related phenotypes in patients with a 16p11.2 deletion.

We studied the presence of benign infantile epilepsy (BIE), paroxysmal kinesigenic dyskinesia (PKD), and PKD with infantile convulsions (PKD/IC) in patients with a 16p11.2 deletion including PRRT2 or with a PRRT2 loss-of-function sequence variant. Index patients were recruited from seven Dutch university hospitals.

The phenotypic spectrum of proximal 6q deletions based on a large cohort derived from social media and literature reports.

Proximal 6q (6q11-q15) deletions are extremely rare and little is known about their phenotypic consequences. Since parents and caregivers now use social media to seek information on rare disorders, the Chromosome 6 Project has successfully collaborated with a Facebook group to collect data on individuals worldwide. Here we describe a cohort of 20 newly identified individuals and 25 literature cases with a proximal 6q deletion.