Gene-disruptive mutations contribute to the biology of neurodevelopmental disorders (NDDs), but most pathogenic genes are not known. We sequenced 208 candidate genes from >11,730 patients and >2,867 controls. We report 91 genes with an excess of de novo mutations or private disruptive mutations in 5.7% of patients, including 38 novel NDD genes. Drosophila functional assays of a subset bolster their involvement in NDDs. We identify 25 genes that show a bias for autism versus intellectual disability and highlight a network associated with high-functioning autism (FSIQ>100). Clinical follow-up for NAA15, KMT5B, and ASH1L reveals novel syndromic and non-syndromic forms of disease.

We have characterized the disease-causing mutations in the steroid 21-hydroxylase genes of 127 patients with different clinical forms of congenital adrenal hyperplasia, representing 186 unrelated chromosomes. The gene was completely absent on 29.8% of the chromosomes, and this together with the I2 splice (27.7%), I173N (20.8%), V282L (5.4%), and R357W (3.8%) mutations constitute 87.5% of all affected chromosomes. In total, 15 different sequence aberrations combine to form 19 different disease-causing alleles. The results confirm that genotyping is an efficient means of diagnosing steroid 21-hydroxylase deficiency, although special consideration is needed to resolve genotypes when full families are not available. Clinical presentations of the different combinations of mutations indicate that genotyping is reliable for prediction of clinical outcome in patients with 21-hydroxylase deficiency. It is especially helpful in determining whether in utero treatment of affected females is indicated and in classifying the severity of 21-hydroxylase deficiency in children diagnosed through neonatal screening, before symptoms have appeared.

The authors further characterise the 17p13.3 microdeletion and microduplication phenotypic spectrum and describe a smaller critical genomic region allowing identification of candidate genes for the distinctive facial dysmorphism (microdeletions) and autism (microduplications) manifestations.

This overview defines the full clinical spectrum of individuals with ADNP mutations, a specific autism subtype. We show that individuals with mutations in ADNP have many overlapping clinical features that are distinctive from those of other autism and/or intellectual disability syndromes. In addition, our data show preliminary evidence of a correlation between genotype and phenotype.