Association of rare missense variants in the second intracellular loop of NaV1.7 sodium channels with familial autism.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder often accompanied by intellectual disability, language impairment and medical co-morbidities. The heritability of autism is high and multiple genes have been implicated as causal. However, most of these genes have been identified in de novo cases. To further the understanding of familial autism, we performed whole-exome sequencing on five families in which second- and third-degree relatives were affected. By focusing on novel and protein-altering variants, we identified a small set of candidate genes. Among these, a novel private missense C1143F variant in the second intracellular loop of the voltage-gated sodium channel NaV1.7, encoded by the SCN9A gene, was identified in one family. Through electrophysiological analysis, we show that NaV1.7C1143F exhibits partial loss-of-function effects, resulting in slower recovery from inactivation and decreased excitability in cultured cortical neurons. Furthermore, for the same intracellular loop of NaV1.7, we found an excess of rare variants in a case-control variant-burden study. Functional analysis of one of these variants, M932L/V991L, also demonstrated reduced firing in cortical neurons. However, although this variant is rare in Caucasians, it is frequent in Latino population, suggesting that genetic background can alter its effects on phenotype. Although the involvement of the SCN1A and SCN2A genes encoding NaV1.1 and NaV1.2 channels in de novo ASD has previously been demonstrated, our study indicates the involvement of inherited SCN9A variants and partial loss-of-function of NaV1.7 channels in the etiology of rare familial ASD.

Iodine deficiency disorders (IDD) and iodised salt in Assam: a few observations.

PIP: During 1992-1993 in India, a UNICEF-supported survey was conducted in Dibrugarh District of Assam State to determine the prevalence of iodine deficiency disorders (IDD), especially goiter. The prevalence of goiter remained high (42.2%) in Dibrugarh District (65.8% in 1989). 46.95% of all iodated salts had less than the optimum level of iodine (15-29.99 ppm). Storage practices affected the iodine content of the salt. For example, within a month and a half, the iodine content of salt stored in earthenware pots is reduced to about 25%. 82.4% of all women 14-45 years old did not perceive goiter as a disease. 98.13% did not know that iodized salt was available in their neighborhood. Yet, the sale of non-iodized salt has been banned in Assam since 1989. An in-depth study was conducted in Sonitpur and Tinsukia districts to determine whether raw salt was imported from the west coast (e.g., Gujarat) to Assam. Transport of iodized salt in remote areas (e.g., Sadia and Lido) took a long time in Tinsukia and storage in earthenware pots, resulting in deterioration of the quality of salt. Salt is transported to Assam in open wagons, which exposes the salt to the sun and the rains. Wholesalers store salt in thick polythene bags which are in turn kept in covered godowns. Retailers sell the salt from open verandas, which exposes the salt to rain and sun. Household storage practices include plastic or glass jars with or without a cover (80.89% and 12.15%, respectively), gourd shells (1.5%), bamboo containers (2.05%), and earthenware pots (3.41%). The quality of iodized salt sold by fraudulent traders was much lower than that sold by reputed firms. The government of India's IDD program monitors the quality of iodized salt. It provides feedback to the state government. Monitoring should be a systematic and continuous process. Assam's government has set up its own monitoring program, focusing on the household level (salt samples: 64.8%). During 1993-1994, 79.7% of salt samples had a satisfactory level of iodine and 2.7% had no iodine at all.^ieng