| Objective Autism spectrum disorder(ASD)is a neurodevelopmental disorder characterized by deficits in communication and social interaction,as well as restricted,repetitive,and stereotyped behavior patterns.The clinical phenotype of ASD is heterogeneous and according to the head circumference size,ASD can be classified into three subtypes: microcephaly,macrocephaly and normal head circumference.The etiology is rather complex,and the risk mainly comes from genetic factors.This study aimed to explore the clinical and molecular genetic features of microcephalic patients with ASD,so as to improve the understanding of phenotypic and genotypic characteristics of this ASD subtype.Subjects and methods A total of 11 microcephalic patients with ASD diagnosed in The Child Development and Behavior Center,the Third Affiliated Hospital of Sun Yat-sen University from December 2014 to May 2020 were enrolled as the research subjects.Via a pilot clinical cross-sectional study,the clinical data were collected,analyzed and described.Copy number variation(CNV)analysis was performed in all patients,including one by multiples ligation-dependent probe amplification(MLPA),and the other ten,by Cyto Scan HD chip.The six patients with negative CNV finding further underwent high-throughput sequencing analysis,and the positive findings were verified by Sanger sequencing in all family trios.Results 1)In this study,all 11 microcephalic patients with ASD had different degrees of social interaction deficit and cognitive impairment.Among them,63.6%(7/11)had abnormal fetal or perinatal histories,50%(5/10)presented other organ defects,30%(3/10)showed motor retardation,45.5%(5/11)exhibited underweight,while 27.3%(3/11)displayed growth retardation.Moreover,44.4%(4/9)of the patients had non-specific EEG abnormalities,but sharp or spike waves were negative.Brain MRI showed abnormalities in 30%(3/10)of the patients,presenting with abnormal myelination,neuroepithelial cyst and dysgenesis of corpus callosum,as well as widened septum pellucidum,respectively.In addition,abnormal hearing and multiple tics were observed in one patient and another patient(9.1%,1/11),respectively.Personalized education and training were given to the patients,and as a result,their abilities got improved in most cases.2)Likely-pathogenic or pathogenic genetic changes were detected in 6(54.5%)patients.The likely-pathogenic changes were a r r [ h g 1 9 ] 1 1 q 1 3.3-1 3.4(6 9,4 1 5,7 2 5-7 1,8 7 3,2 2 0)×1,a r r [ h g 1 9 ]1 p 3 4.2-3 4.3(40,058,392-42,787,899)×1,arr[hg19] 2q23.1(148,932,570-148,954,778)×1 and a novel missense mutation c.692A>C(p.His231Pro)in FOXG1 gene,and none of them has been reported previously.The pathogenic changes were 16p13.3 microdeletion,and a heterozygous nonsense mutation c.763C>T(p.Arg255*)in DYRK1 A gene.A CNV with unknown significance,arr[hg19]6q24.3(146,315,688-146,377,678)×1,was detected in another patient.Conclusions 1)The microcephalic patients with ASD exhibited considerable clinical and genetic heterogeneity.2)The positive rate of genomic CNV and de novo variants in specific genes in this subtype of ASD patients was as high as 54.5%,suggesting the necessity of genetic testing.3)In this study,three new genomic CNV and a novel missense mutation of FOXG1 gene were identified,which enriched the genetic etiological spectrum of ASD with microcephaly. |
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