BACKGROUND Autism spectrum disorders(ASD)represent a substantial social problem affecting at least 1 in 100 children worldwide.These conditions are very often accompanied by intellectual disability(ID)and speech delay...BACKGROUND Autism spectrum disorders(ASD)represent a substantial social problem affecting at least 1 in 100 children worldwide.These conditions are very often accompanied by intellectual disability(ID)and speech delay;thus,they can be considered within a clinical continuum of neurodevelopmental disorders.Given the high heterogeneity of ASD,the subjective nature of diagnostic criteria,and the presence of phenocopies,identifying genetic determinants of these disorders remains a challenge.AIM To investigate the spectrum and frequency of rare genetic variants in genes with proven association with ASD in Russian children.METHODS 110 patients from 106 families were recruited into the study mean age at diagnosis 6 years;boy-to-girl ratio 3:1.Most of the patients(84%)demonstrated a combination of ASD with developmental delay(DD)or ID.Patients with syndromic features were subjected to the chromosomal microarray analysis.The remained children underwent clinical exome sequencing aimed at identifying presumably monogenic causes of ASD.The study focused on rare(minor allele frequency≤0.001)variants affecting high-confidence ASD-associated genes.RESULTS Pathogenic copy number variations were detected in three(7%)of the patients examined.Clinical exome sequencing revealed pathogenic/likely pathogenic variants in 12 of 105 cases(11%),indicating the presence of monogenic syndromes with established clinical significance(Pitt-Hopkins syndrome,ZTTK syndrome,syndromic X-linked ID of Billuart type,Snijders-Blok-Campeau,Helsmoortel-van der Aa,Coffin-Siris,Clark-Baraitser,Keefstra syndromes,etc.).In addition,27 patients(26%)had 37 rare variants of unknown clinical significance in DSCAM,SHANK2,AUTS2,ADNP,ANKRD11,APBA2,ARID1B,ASTN2,ATRX,SCN1A,CHD2,DEAF1,EHMT1,GRIN2B,NBEA,NR4A2,TRIO,TRIP12,POGZ,EP300,FOXP1,PCDH19,GRIN2A,NCKAP1,and CHD8 genes.No specific variant was detected more than once in unrelated patients.Among the genes with rare variants found in 2 or more patients were TRIP12(n=4),AUTS2(n=3),ARID1B(n=3),PCDH19(n=3),EP300(n=3),TRIO(n=2),ASTN2(n=2),EHMT1(n=2),and CHD2(n=2).Of note,5 male ASD/DD patients from 3 unrelated families had PCDH19 missense variants,confirming that at least some hemizygous males with non-mosaic PCDH19 variants may present with neurobehavioral abnormalities.These variants did not cause epilepsy restricted to females in patients’mothers or sisters.CONCLUSION These data confirm a tremendous diversity of genetic causes of ASD.Clinical exome sequencing may serve as a reasonable alternative to whole-exome sequencing.展开更多
2008年澳大利亚Dibbens等首次在限于女性的癫痫伴智力低下(epilepsy and mental retardation limited to females, EFMR)家系中报道其致病基因为PCDH19基因,该基因编码原钙黏蛋白19(protocadherin 19)。PCDH19基因相关癫痫(以下简称“PC...2008年澳大利亚Dibbens等首次在限于女性的癫痫伴智力低下(epilepsy and mental retardation limited to females, EFMR)家系中报道其致病基因为PCDH19基因,该基因编码原钙黏蛋白19(protocadherin 19)。PCDH19基因相关癫痫(以下简称“PCDH19癫痫”)是一种特殊的X连锁遗传性癫痫,多见于女性杂合子发病,少数男性嵌合体也可发病,而男性半合子不发病。展开更多
基金Supported by the Russian Science Foundation Grant,No.24-45-00067.
文摘BACKGROUND Autism spectrum disorders(ASD)represent a substantial social problem affecting at least 1 in 100 children worldwide.These conditions are very often accompanied by intellectual disability(ID)and speech delay;thus,they can be considered within a clinical continuum of neurodevelopmental disorders.Given the high heterogeneity of ASD,the subjective nature of diagnostic criteria,and the presence of phenocopies,identifying genetic determinants of these disorders remains a challenge.AIM To investigate the spectrum and frequency of rare genetic variants in genes with proven association with ASD in Russian children.METHODS 110 patients from 106 families were recruited into the study mean age at diagnosis 6 years;boy-to-girl ratio 3:1.Most of the patients(84%)demonstrated a combination of ASD with developmental delay(DD)or ID.Patients with syndromic features were subjected to the chromosomal microarray analysis.The remained children underwent clinical exome sequencing aimed at identifying presumably monogenic causes of ASD.The study focused on rare(minor allele frequency≤0.001)variants affecting high-confidence ASD-associated genes.RESULTS Pathogenic copy number variations were detected in three(7%)of the patients examined.Clinical exome sequencing revealed pathogenic/likely pathogenic variants in 12 of 105 cases(11%),indicating the presence of monogenic syndromes with established clinical significance(Pitt-Hopkins syndrome,ZTTK syndrome,syndromic X-linked ID of Billuart type,Snijders-Blok-Campeau,Helsmoortel-van der Aa,Coffin-Siris,Clark-Baraitser,Keefstra syndromes,etc.).In addition,27 patients(26%)had 37 rare variants of unknown clinical significance in DSCAM,SHANK2,AUTS2,ADNP,ANKRD11,APBA2,ARID1B,ASTN2,ATRX,SCN1A,CHD2,DEAF1,EHMT1,GRIN2B,NBEA,NR4A2,TRIO,TRIP12,POGZ,EP300,FOXP1,PCDH19,GRIN2A,NCKAP1,and CHD8 genes.No specific variant was detected more than once in unrelated patients.Among the genes with rare variants found in 2 or more patients were TRIP12(n=4),AUTS2(n=3),ARID1B(n=3),PCDH19(n=3),EP300(n=3),TRIO(n=2),ASTN2(n=2),EHMT1(n=2),and CHD2(n=2).Of note,5 male ASD/DD patients from 3 unrelated families had PCDH19 missense variants,confirming that at least some hemizygous males with non-mosaic PCDH19 variants may present with neurobehavioral abnormalities.These variants did not cause epilepsy restricted to females in patients’mothers or sisters.CONCLUSION These data confirm a tremendous diversity of genetic causes of ASD.Clinical exome sequencing may serve as a reasonable alternative to whole-exome sequencing.
文摘2008年澳大利亚Dibbens等首次在限于女性的癫痫伴智力低下(epilepsy and mental retardation limited to females, EFMR)家系中报道其致病基因为PCDH19基因,该基因编码原钙黏蛋白19(protocadherin 19)。PCDH19基因相关癫痫(以下简称“PCDH19癫痫”)是一种特殊的X连锁遗传性癫痫,多见于女性杂合子发病,少数男性嵌合体也可发病,而男性半合子不发病。
