Kleefstra syndrome: Impact on parents.

BACKGROUND: Kleefstra syndrome (KS) is associated with developmental delay, autism, intellectual disability, psychosis, and regression. Research has not been conducted to assess the impact of KS on parents. OBJECTIVE/HYPOTHESIS: A mixed-method study was conducted to assess the impact on parental well-being by evaluating parents' well-being, identifying factors of parental experience predicting well-being, and exploring the parental experience. METHODS: Parents completed an online survey containing the PedsQL™ Family Impact Module (FIM) and a questionnaire created by the researchers. One-Way T-Test compared parents of children with KS to parents of children with Prader-Willi syndrome (PWS). Multiple linear regression used parents' total scale scores on PedsQL™ FIM to identify factors influencing parental well-being. Constant comparative analysis used open-ended responses to explore the parental experience of having a child with KS. RESULTS: Parents of children with KS had statistically lower scores in daily activity and social functioning, but statistically higher scores in communication and emotional functioning compared to parents of children with PWS. However, the power was below 0.80, meaning additional research needs to be completed to confirm these findings. The linear multiple regression was not significant. Most importantly, the themes of establishing the diagnosis, importance of knowledge, sense of community, KS and relationships with others, how life changed, and what the future will hold, characterized the parental experience. CONCLUSIONS: Knowledge and support were important to parents who had a child recently diagnosed with KS. Therefore, parents should be provided resources about KS and support groups at diagnosis.

The increasing challenge of genetic counseling for cystic fibrosis.

Genetic counseling for cystic fibrosis (CF) is challenged by intricate molecular mechanisms, complex phenotypes, and psychosocial needs. CFTR variant interpretation has become critical; this manuscript examines variant nomenclature and classes, as well as opportunities and challenges posed by genetic technologies and genotype-directed therapies. With post-graduate training in medical genetics and counseling, genetic counselors educate patients and families, facilitate testing and interpretation, and help integrate genetic information into diagnosis and treatment. They support families, ranging from carrier couples or new parents, to children understanding their disease, to adults with CF contemplating reproduction. The changing face of CF increasingly highlights the critical importance of genetic information to patients and their families. Genetic counselors are uniquely poised to translate this information in diagnostics and personalized care. Genetic counselors straddle molecular and clinical realms, helping patients adapt, plan, and gain access to appropriate therapies.

Mutations in SCN3A cause early infantile epileptic encephalopathy.

OBJECTIVE: Voltage-gated sodium (Na+ ) channels underlie action potential generation and propagation and hence are central to the regulation of excitability in the nervous system. Mutations in the genes SCN1A, SCN2A, and SCN8A, encoding the Na+ channel pore-forming (α) subunits Nav1.1, 1.2, and 1.6, respectively, and SCN1B, encoding the accessory subunit ß1 , are established causes of genetic epilepsies. SCN3A, encoding Nav1.3, is known to be highly expressed in brain, but has not previously been linked to early infantile epileptic encephalopathy. Here, we describe a cohort of 4 patients with epileptic encephalopathy and heterozygous de novo missense variants in SCN3A (p.Ile875Thr in 2 cases, p.Pro1333Leu, and p.Val1769Ala). METHODS: All patients presented with treatment-resistant epilepsy in the first year of life, severe to profound intellectual disability, and in 2 cases (both with the variant p.Ile875Thr), diffuse polymicrogyria. RESULTS: Electrophysiological recordings of mutant channels revealed prominent gain of channel function, with a markedly increased amplitude of the slowly inactivating current component, and for 2 of 3 mutants (p.Ile875Thr and p.Pro1333Leu), a leftward shift in the voltage dependence of activation to more hyperpolarized potentials. Gain of function was not observed for Nav1.3 variants known or presumed to be inherited (p.Arg1642Cys and p.Lys1799Gln). The antiseizure medications phenytoin and lacosamide selectively blocked slowly inactivating over transient current in wild-type and mutant Nav1.3 channels. INTERPRETATION: These findings establish SCN3A as a new gene for infantile epileptic encephalopathy and suggest a potential pharmacologic intervention. These findings also reinforce the role of Nav1.3 as an important regulator of neuronal excitability in the developing brain, while providing additional insight into mechanisms of slow inactivation of Nav1.3. Ann Neurol 2018;83:703-717.