Novel de novo heterozygous mutation on SYNGAP1 from the Indian population

: 7 Background : Exome sequencing is a prominent tool to identify novel and deleterious 8 mutations which could be nonsense, frameshift, and canonical splice-site mutations in a 9 specific gene. De novo mutations in SYNGAP1 , which codes for synaptic RAS-GTPase 10 activating the protein, causes Intellectual disability (ID) and Autism Spectrum Disorder (ASD). 11 SYNGAP1 related ASD/ID is one of the rare diseases that is detrimental to the normal neuronal 12 developmental and disrupts the global development of a child. 13 Results: We report a case of a child of 2-year old with global developmental delay, 14 microcephaly subtle dysmorphism, absence seizures, disrupted sleep, delay in learning a 15 language, and eating problems. Upon further validation, the child has a few traits of ASD. Here, 16 based on focused exome sequencing, we report a de novo heterozygous mutation in SYNGAP1 17 exon 11 with c. 1861 C>T (p.arg612ter). Currently, the child is on atorvastatin and has shown 18 considerable improvement in global behaviour and cognitive development. The long-term 19 follow up of the child’s development would contribute to the already existing knowledge of 20 the developmental trajectory in individuals with SYNGAP1 heterozygous mutation. 21 Conclusion: In this report, we discuss the finding of a novel mutation in one of the genes, 22 SYNGAP1 , implicated in ASD/ID. In addition, we discuss the current treatment prescribed to 23 the patient and the progress of global developmental of the child.


Background:
26 ID and ASD are common debilitating neurodevelopmental disorders defined by the presence 27 of significant limitations in cognitive and emotional behaviours, and global delay in 28 development associated with epilepsy (1-4). Heterozygous mutations in SYNGAP1 causing ID 29 and ASD was first reported in 2009 (1). Since then, many exome sequencings studies have 30 identified novel mutations in SYNGAP1 (3,5,6). Most affected individuals have de novo 31 mutations with truncating mutations, but missense mutations, chromosomal aberrations and 32 microdeletions in SYNGAP1 are reported (7-10). SYNGAP1-related ASD/ID is recently 33 categorised as rare-diseases.

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SYNGAP1 on chromosome 6p21.32 (OMIM 603384) encodes a synaptic RAS-GTPase 35 activating protein expressed mainly in the excitatory neurons (11,12). SYNGAP1 is a vital 36 regulator of NMDAR-mediated signalling mechanism in the neurons (13-15). Studies using 37 mouse model have shown that SYNGAP1 heterozygous mutation leads to precarious 38 accelerated maturation of dendritic spines, abnormal neuronal branching, and alters the critical 39 period of development (16)(17)(18). Loss of function of SYNGAP1 is associated with impaired 40 learning and memory, emotional, and other behavioural deficits (19,20). Therefore, the normal 41 function of SYNGAP1 is necessary for proper brain development, particularly during the 42 critical period of development (milestones).

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This report is the first to discuss a patient with heterozygous SYNGAP1 heterozygous mutation 44 from the Indian cohort. Briefly, the boy of 2-year of age (at the time of diagnosis) was presented 45 with global developmental delay, absence seizure, disrupted sleep, delay in learning a 46 language, and eating problems.

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He had microcephaly subtle dysmorphism including hypertelorism, long philtrum, and long 52 ears with mild hypotonia without significant family and perinatal history. His Developmental 53 Quotient (DQ) corresponded to 8 months and in the range of 60-79, which was categorised as 54 below average (Table 1). When the patient arrived at the clinic, frequent absence seizure was 55 observed. The patient was presented with disrupted sleep (mainly due to seizures), hypotonia, 56 difficulty in swallowing, delayed speech, delay in the ability to walk, bouts of aggression often 57 associated with fits of rage, heightened sensitivity (scared) to sounds and toys, constipation, 58 repeated hand gesture followed by mild slapping on his mouth, selective hearing (pays attention 59 only if the instruction is related to the current activity), and does not fall into the DSM-V criteria 60 for Autism Spectrum Disorder. Overall, the patient has global developmental delays, 61 particularly speech and motor milestones, and exhibited behavioural difficulties. Both the 62 parents are well-educated and had no prior family history of brain-related disorder or disease. 63 However, the mother suffered from low blood pressure and was on medication throughout 64 pregnancy, and the patient was kept in light therapy for 1.5 days after birth. internal databases. This is the first report to show a novel mutation in SYNGAP1 gene and the 85 first report on SYNGAP1 heterozygous mutation from the Indian cohort. We had sequenced 86 genes implicated in epilepsy encephalopathy and ID/ASD such as TSC1, MECP2, SLC2A1 but 87 no alteration was identified (Table 2). However, more studies are required to understand further 88 how this mutation affects neuronal development and 89 Therapeutic strategy: 90 The boy is currently on Lamectec 5 mg (10 tablets a day), Sodium Valproate, Encorate (12 ml 91 a day), Ethosuximide, Absenz (5 ml) a day. His seizures are in control; however, due to growth 92 spurts, the dosages had to be increased as suggested by the doctor. Presently, he is given unclear whether the mutation on SYNGAP1 existed in India. Here, we report a first mutation 106 identified from the Indian cohort.

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The patient was presented with global developmental delay, absence epilepsy, sleeping and 108 eating problems along with other phenotypes related to ID/ASD. His overall DQ corresponded 109 to 8 months and in the range of 60-79 which was categorised as below average, which was 110 within the range of ID/ASD. Routine biochemical tests did not reveal any alterations suggesting 111 that the phenotype observed was due to genetic mutations related to brain development.    The parents have given their consent to proceed with publication of the data obtained from the 184 child. 186 All authors have agreed to publish these data.

Availability of data and materials
188 Anonymised data will be shared by request from any qualified investigator.