Finding underlying genetic mechanisms of two patients with autism spectrum disorder carrying familial apparently balanced chromosomal translocations

Toraman, Bayram; Bilginer, Samiye Çilem; Hesapçıoğlu, Selma Tural; Göker, Zeynep; Soykam, Hüseyin Okan; Ergüner, Bekir; Dinçer, Tuba; Yildiz, Gokhan; Ünsal, Serbülent; Kasap, Burak Kaan; Kandil, Sema; Kalay, Ersan

doi:10.1002/jgm.3322

Cited by 4 publications

(1 citation statement)

References 104 publications

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“…Moreover, their offspring would have a continuous spectrum of phenotypic effects of pathogenic CNVs, from adaptive traits to underlying cause of disease to embryonic lethality risk of an associated reciprocal translocation [28]. Translocations have also been productive in identifying new candidate genes underlying common clinical phenotypes that may arise from dysfunction of any number of genes, as in Alveolar Soft-Part Sarcoma [29], acute myeloid leukemia [30], and autism [31].…”

Section: Discussionmentioning

confidence: 99%

Exome and Genome Sequencing to Unravel the Precise Breakpoints of Partial Trisomy 6q and Partial Monosomy 2q

Zhang

Cui

Yang

et al. 2023

Preprint

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Background Uncovering the precise breakpoints of subchromosomal deletions and duplications could help to clarify the spectrum of the unbalanced translocation and detect the cause of congenital malformations and mental retardation in Children. However, it is challenging to capture the large segment of genomic variants using exome sequencing techniques. Here, we combine exome and genome sequencing techniques to secure the accurate breakpoints of a proband with both heterozygous microduplications in the 6q 25.3-q27region and microdeletions in the 2q37.1-q37.3 region. Case presentation Here, the Whole Exon Sequencing (WES) got clues about the pathological CNVs at chromosomes 2q and 6q but failed to detect the precisely related location. Then we applied the genome sequencing, as copy number variations sequencing (CNV-seq), to compensate for determining the accurate breakpoint sites. These sites could also be ensured by Oxford Nanopore sequencing (ONT) and Optical genome mapping (OGM). The proband showed de novo heterozygous copy number deletion with del(2)(q37.1q37.3)chr2:g.232963568_24305260del and copy number duplication with dup(6)(q25.3q27)chr6:g.158730978_170930050dup which derived from parental balanced translocation t(2;6)(q37.1-37.3;q25.3-27). Different from previous reports about the translocation of 2q and 6q, we get the accurate breakpoint, and the proband showed severe congenital cranial dysinnervation disorders(CCDD), and abnormal thorax development. Conclusions We conclude that it is highly efficient to combine exome and genome sequencing techniques to secure precise breakpoints of subchromosomal deletions and duplications derived from balanced translocation. And the genome sequencing techniques could be CNV-seq, ONT, or OGM.

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Section: Discussionmentioning

confidence: 99%

Exome and Genome Sequencing to Unravel the Precise Breakpoints of Partial Trisomy 6q and Partial Monosomy 2q

Zhang

Cui

Yang

et al. 2023

Preprint

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Exome and genome sequencing to unravel the precise breakpoints of partial trisomy 6q and partial Monosomy 2q

Zhang,

Cui,

Yang

et al. 2023

BMC Pediatr

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Background Patients with complex phenotypes and a chromosomal translocation are particularly challenging, since several potentially pathogenic mechanisms need to be investigated. Case presentation Here, we combined exome and genome sequencing techniques to identify the precise breakpoints of heterozygous microduplications in the 6q25.3-q27 region and microdeletions in the 2q37.1-q37.3 region in a proband. The 5-year-old girl exhibited a severe form of congenital cranial dysinnervation disorder (CCDD) in addition to skeletal dysmorphism anomalies and severe intellectual disability. This is the second case affecting chromosomes 2q and 6q. The individual’s karyotype showed an unbalanced translocation 46,XX,del(2)t(2;6)(q37.1;q25.3), which was inherited from her unaffected father [46,XY,t(2;6)(q37.1;q25.3)]. We also obtained the precise breakpoints of a de novo heterozygous copy number deletion [del(2)(q37.1q37.3)chr2:g.232963568_24305260del] and a copy number duplication [dup(6)(q25.3q27)chr6:g.158730978_170930050dup]. The parental origin of the observed balanced translocation was not clear because the parents declined genetic testing. Conclusion Patients with a 2q37 deletion and 6q25.3 duplication may exhibit severe significant neurological and skeletal dysmorphisms, and the utilization of exome and genome sequencing techniques has the potential to unveil the entire translocation of the CNV and the precise breakpoint.

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Genome Sequencing Identifies 13 Novel Candidate Risk Genes for Autism Spectrum Disorder in a Qatari Cohort

Ben-Mahmoud,

Gupta,

Abdelaleem

et al. 2024

IJMS

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Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social communication, restricted interests, and repetitive behaviors. Despite considerable research efforts, the genetic complexity of ASD remains poorly understood, complicating diagnosis and treatment, especially in the Arab population, with its genetic diversity linked to migration, tribal structures, and high consanguinity. To address the scarcity of ASD genetic data in the Middle East, we conducted genome sequencing (GS) on 50 ASD subjects and their unaffected parents. Our analysis revealed 37 single-nucleotide variants from 36 candidate genes and over 200 CGG repeats in the FMR1 gene in one subject. The identified variants were classified as uncertain, likely pathogenic, or pathogenic based on in-silico algorithms and ACMG criteria. Notably, 52% of the identified variants were homozygous, indicating a recessive genetic architecture to ASD in this population. This finding underscores the significant impact of high consanguinity within the Qatari population, which could be utilized in genetic counseling/screening program in Qatar. We also discovered single nucleotide variants in 13 novel genes not previously associated with ASD: ARSF, BAHD1, CHST7, CUL2, FRMPD3, KCNC4, LFNG, RGS4, RNF133, SCRN2, SLC12A8, USP24, and ZNF746. Our investigation categorized the candidate genes into seven groups, highlighting their roles in cognitive development, including the ubiquitin pathway, transcription factors, solute carriers, kinases, glutamate receptors, chromatin remodelers, and ion channels.

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Finding underlying genetic mechanisms of two patients with autism spectrum disorder carrying familial apparently balanced chromosomal translocations

Cited by 4 publications

References 104 publications

Exome and Genome Sequencing to Unravel the Precise Breakpoints of Partial Trisomy 6q and Partial Monosomy 2q

Exome and Genome Sequencing to Unravel the Precise Breakpoints of Partial Trisomy 6q and Partial Monosomy 2q

Exome and genome sequencing to unravel the precise breakpoints of partial trisomy 6q and partial Monosomy 2q

Genome Sequencing Identifies 13 Novel Candidate Risk Genes for Autism Spectrum Disorder in a Qatari Cohort

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