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A novel nonsense homozygous variant in the NLGN1 gene found in a pair of monozygotic twin brothers with intellectual disability and autism

To the Editor: Since neuroligines 3 (NLGN3) and 4 (NLGN4) were first identified as risk genes for autism spectrum disorder (ASD), some authors have studied its implication in this condition. Recently, Nakanishi et al demonstrated for the first time the functional significance of rare neuroligin 1 (NLGN1) variants in autism. To date (August 2018), only 11 variants have been identified in NLGN1, (https://portal.biobaseinternational.com/hgmd/pro/search_gene.php) none of them are nonsense and all were heterozygous variants. We present for the first time a novel nonsense homozygous variant in the NLGN1 gene (c.74T>A;p.Leu25*) found in two monozygotic twin brothers. The patients were the only children of phenotypically and psychologically normal first cousins parents, born with normal phenotype. Gestation and delivery was uneventful. Soon after birth, developmental delay was noted. At the age of 3, they showed behavioural problems related to ASD and had an irritative and aggressive behaviour. At 5 years they were at the normal centile for weight, height and head circumference and had no obvious dysmorphic features. They understood instructions and said short sentences with few words, although they pronounced them badly. At that age, the aggressive behaviour diminished in both. In the following years until we saw them at the genetics consultation at the age of 12, both patients were making progress but always slowly. They were described as having an interesting communication and interaction between them, always being intense and special. They developed stereotypical and repetitive behaviours and interests, consistent with ASD. Goodenough tests performed in both brothers showed a mental age some years below their real age (IQ = 68). Last assessment at our consultation at 16 years, revealed that they have a clear language although fast and in a mechanical way. They were also able to read and write but they still have social interaction difficulties, stereotypes, obsessive symptoms as well as intellectual disability (ID). Written informed consent was obtained from the parents and genetic studies were approved by the Ethics Committee on Clinical Research of the Autonomous Community of the Basque Country. FMR1 test and Array-CGH were performed and yielded normal results. Whole exome sequencing was performed with the strategy of family trio using the Ion Proton sequencer (Thermo Fisher Scientific, P/N 4476610, Waltham, MA, USA). Torrent Suite software (version 4.4.3) and the TMAP software were used to align reads to the UCSC hg19 reference sequence. After uploading BAM files to Ion Reporter (version 4.4.2) and launching “AmpliSeq Exome trio” protocol, all variants were identified. They were filtered for genes associated with ID/ASD, and according to the recessive model of inheritance. Among the variants found, we identified a novel nonsense homozygous variant in the NLGN1 gene (c.74T>A; p.Leu25*) (NM_014932.3) (Figure 1) in the proband, for which both parents were heterozygous.