Interstitial 1q21.1 Microdeletion Is Associated with Severe Skeletal Anomalies, Dysmorphic Face and Moderate Intellectual Disability

Gamba, Bruno Faulin; Zechi-Ceide, Roseli Maria; Kokitsu-Nakata, Nancy Mizue; Vendramini-Pittoli, Siulan; Rosenberg, Carla; Santos, Ana C.V. Krepischi; Ribeiro-Bicudo, Lucilene Arilho; Richieri-Costa, Antônio

doi:10.1159/000450971

Cited by 19 publications

(13 citation statements)

References 20 publications

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“…Three CNVs were classified as clinically relevant based on relevant phenotypes observed in heterozygous knockout mice models. These include: (a) a heterozygous 400‐kb deletion (chr1:145382349‐145765424) impacting 21 genes including RBM8A , haploinsufficiency of which disrupts embryonic cortical development and results in microcephaly in mice and intellectual disability in humans; (b) a heterozygous deletion of the last exon of MDGA2 , haploinsufficiency of which leads to an autism‐like phenotype including stereotypy, aberrant social interactions and impaired memory in mice and which is considered a candidate gene for autism in humans and (c) a microduplication of a regulatory region and exon 1 of HOMER1 , encoding a protein that regulates the functional assembly of postsynaptic density proteins at glutamatergic synapses, and haploinsufficiency of which in mice leads to increased aggression in social interactions . A single individual (288868) with a similar microduplication demonstrating aggressive behavior and intellectual disability is reported in the DECIPHER database.…”

Section: Resultsmentioning

confidence: 99%

Rare copy number variation in extremely impulsively violent males

Vevera

Zarrei

Hartmannová

et al. 2018

Genes Brain and Behavior

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The genetic correlates of extreme impulsive violence are poorly understood, and there have been no studies that have systematically characterized a large group of affected individuals both clinically and genetically. We performed a genome‐wide rare copy number variant (CNV) analysis in 281 males from four Czech prisons who met strict clinical criteria for extreme impulsive violence. Inclusion criteria included age ≥ 18 years, an ICD‐10 diagnosis of Dissocial Personality Disorder, and the absence of an organic brain disorder. Participants underwent a structured psychiatric assessment to diagnose extreme impulsive violence and then provided a blood sample for genetic analysis. DNA was genotyped and CNVs were identified using Illumina HumanOmni2.5 single‐nucleotide polymorphism array platform. Comparing with 10851 external population controls, we identified 828 rare CNVs (frequency ≤ 0.1% among control samples) in 264 participants. The CNVs impacted 754 genes, with 124 genes impacted more than once (2‐25 times). Many of these genes are associated with autosomal dominant or X‐linked disorders affecting adult behavior, cognition, learning, intelligence, specifically expressed in the brain and relevant to synapses, neurodevelopment, neurodegeneration, obesity and neuropsychiatric phenotypes. Specifically, we identified 31 CNVs of clinical relevance in 31 individuals, 59 likely clinically relevant CNVs in 49 individuals, and 17 recurrent CNVs in 65 individuals. Thus, 123 of 281 (44%) individuals had one to several rare CNVs that were indirectly or directly relevant to impulsive violence. Extreme impulsive violence is genetically heterogeneous and genomic analysis is likely required to identify, further research and specifically treat the causes in affected individuals.

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Section: Resultsmentioning

confidence: 99%

Rare copy number variation in extremely impulsively violent males

Vevera

Zarrei

Hartmannová

et al. 2018

Genes Brain and Behavior

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“…21 RBM8A haploinsufficiency has been linked to a condition known as thrombocytopenia-absent radius syndrome which presents skeletal anomalies, craniofacial defects, and microcephaly. 22,23 HNRNPR mutations are associated with Au-Kline syndrome, Bain type mental retardation, and early infantile epileptic encephalopathy-54, which are characterized by intellectual disability, seizures, and abnormalities of the skeleton and face. 24 Finally, RBM10 mutations have been linked to TARP syndrome, a rare condition that causes Talipes equinovarus (clubfoot), Atrial septal defect, Robin sequence and Persistence left superior vena cava.…”

Section: Craniofacial Disordersmentioning

confidence: 99%

Spliceosomopathies: Diseases and mechanisms

Griffin

Saint-Jeannet

2020

Developmental Dynamics

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The spliceosome is a complex of RNA and proteins that function together to identify intron‐exon junctions in precursor messenger‐RNAs, splice out the introns, and join the flanking exons. Mutations in any one of the genes encoding the proteins that make up the spliceosome may result in diseases known as spliceosomopathies. While the spliceosome is active in all cell types, with the majority of the proteins presumably expressed ubiquitously, spliceosomopathies tend to be tissue‐specific as a result of germ line or somatic mutations, with phenotypes affecting primarily the retina in retinitis pigmentosa, hematopoietic lineages in myelodysplastic syndromes, or the craniofacial skeleton in mandibulofacial dysostosis. Here we describe the major spliceosomopathies, review the proposed mechanisms underlying retinitis pigmentosa and myelodysplastic syndromes, and discuss how this knowledge may inform our understanding of craniofacial spliceosomopathies.

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“…The pregnancy was complicated by a spinal abnormality noted on ultrasound. While the phenotype of 1q21.1 deletion syndrome (OMIM #612474) can be variable, patient 6 presented with findings consistent with this diagnosis including microcephaly, and skeletal anomalies including scoliosis (Bernier et al, 2016; Gamba et al, 2016). The patient also presented with features consistent with 22q11.2DS including feeding difficulties, constipation, short stature, laryngeal cleft, developmental delay, low IgM and moderate CD8 T cell lymphopenia, anterior arch C1 hypoplasia, velopharyngeal insufficiency and hypernasal speech, underdeveloped alae nasi, and long, slender, tapered fingers.…”

Section: Resultsmentioning

confidence: 87%

22q and two: 22q11.2 deletion syndrome and coexisting conditions

Cohen

Crowley

McGinn

et al. 2018

American J of Med Genetics Pt A

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22q11.2 deletion syndrome (DS) is the most frequent copy number variant (CNV) affecting ~1/1,000 fetuses and ~1/2,000–4,000 children, resulting in recognizable but variable findings across multiple organ systems. Patients with atypical features should prompt consideration of coexisting diagnoses due to additional genome-wide mutations, CNVs, or mutations/CNVs on the other allele, unmasking autosomal recessive conditions. Importantly, a dual diagnosis compounds symptoms and impacts management. We previously reported seven patients with 22q11.2DS and: SCID, Trisomy 8 mosaicism, Bernard-Soulier, and CEDNIK syndromes. Here we present six additional unreported patients with 22q11.2DS and concurrent diagnoses. Records on 1,422 patients with 22q11.2DS, identified via FISH, microarray, or MLPA, followed in our 22q and You Center at the Children’s Hospital of Philadelphia (CHOP) were reviewed to identify a dual diagnosis. In addition to our seven previously reported cases, we identified an additional six with 22q11.2DS and another coexisting condition identified via: molecular/cytogenetic studies, newborn screening, coagulation factor studies, or enzyme testing; these include CHARGE syndrome (CHD7 mutation), cystic fibrosis, a maternally inherited 17q12 deletion, G6PD deficiency, von Willebrand disease, and 1q21.1 deletion, resulting in an incidence of dual diagnoses at our center of 0.9%. The range of dual diagnoses identified in our cohort is notable, medically actionable, and may alter long-term outcome and recurrence risk counseling. Thus, our findings may support testing patients with 22q11.2DS using a combination of microarray, mutational analysis of the other allele/WES, to ensure appropriate personalized care, as formulating medical management decisions hinges on establishing the correct diagnoses in their entirety.

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Interstitial 1q21.1 Microdeletion Is Associated with Severe Skeletal Anomalies, Dysmorphic Face and Moderate Intellectual Disability

Cited by 19 publications

References 20 publications

Rare copy number variation in extremely impulsively violent males

Rare copy number variation in extremely impulsively violent males

Spliceosomopathies: Diseases and mechanisms

22q and two: 22q11.2 deletion syndrome and coexisting conditions

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