8p23.1 recurrent region (includes GATA4)

  • 3
    Haplo
    Score
  • 2
    Triplo
    Score

Region Facts

Region Name
8p23.1 recurrent region (includes GATA4)
Cytoband
8p23.1
Genomic Coordinates
GRCh37/hg19 chr8:8100064-11766329 NCBI Ensembl UCSC
GRCh38/hg38 chr8:8242542-11908820 NCBI Ensembl UCSC

Dosage Sensitivity Summary (Region)

Dosage ID:
ISCA-37423
Curation Status:
Complete
Issue Type:
Dosage Curation - Region
Description:
This review refers to the 8p23.1 recurrent region (includes GATA4). Many reports of CNVs involving this region in the literature describe variable breakpoints and genomic content, in part due to the complexity of flanking repeat regions. This curation is limited to cases with typical recurrent CNVs characterized by genomic CNV analysis (e.g. aCGH or SNP-array). Note that genes used as landmarks are not necessarily causative of the phenotype(s) associated with the region.
Haploinsufficiency:
Sufficient Evidence for Haploinsufficiency (3)
Triplosensitivity:
Emerging Evidence for Triplosensitivity (2)
Related Links:
Last Evaluated:
06/10/2022

Haploinsufficiency (HI) Score Details

HI Score:
3
HI Evidence Strength:
Sufficient Evidence for Haploinsufficiency (Disclaimer)
HI Evidence:
  • PUBMED: 20969981
    Ballarati et al. (2011) identified a de novo recurrent 8p23.1 deletion by aCGH in a patient with cardiac malformation (atrial septal defect), pulmonary stenosis, mild developmental delay, ADHD, and craniofacial dysmorphism, and reviewed clinical findings in 50 previously published cases with overlapping deletions (most of which were not characterized by array- breakpoints uncertain).
  • PUBMED: 23239632
    Guimiot et al. (2013) reported a mother and fetus with an apparent (reported as 5.6 Mb, but visually appearing to be a typical) recurrent 8p23.1 deletion identified by clinical SNP-array who both had congenital heart malformations involving the atrioventricular valvulo-septal complex. The mother also had moderate intellectual disability.
  • PUBMED: 19606479
    Wat et al. (2009) reported 4 individuals (including 2 monozygotic twins) with apparent recurrent 8p23.1 deletions identified by clinical aCGH, all of whom were diagnosed prenatally with complex congenital heart defects. Additional features amongst these patients included dysmorphic features, congenital diaphragmatic hernia, two-vessel umbilical cord, and intrauterine growth restriction. All deletions were de novo.
HI Evidence Comments:
Deletion of 8p23.1 including GATA4 is associated with a phenotype that includes congenital heart defects (particularly ASD, VSD, and pulmonary stenosis), diaphragmatic hernia, craniofacial dysmorphism, microcephaly, and developmental delay/intellectual disability. Additional findings may include vertebral defects, renal anomalies, polydactyly, seizures, and behavioral difficulties. The majority of 8p23 deletions are de novo, although inherited cases have been reported. Case-control comparison studies have shown enrichment of this deletion in clinical populations. Therefore, the haploinsufficiency score is 3. Additional relevant literature is summarized below: Case-Control Studies: PMID: 25217958 Coe et al. (2014) performed a large-scale case-control comparison study of the relative prevalence of CNVs in children with developmental delay/intellectual disability, multiple congenital anomalies, and other developmental phenotypes compared to controls. Deletions of the 8p23.1 region were observed in 8/29,085 cases versus 0/19,584 controls (p=0.0163; LR: Inf, 95% CI: 1.47-Inf), demonstrating enrichment of this CNV in the clinical population. See also Cooper et al. (2011) PMID 21841781, which used an overlapping (older) dataset. Predisposing Haplotype Studies: Additionally, there is a predisposing haplotype for genomic rearrangements in 8p23.1 that has variable frequency across different human populations (see PMIDs 27803192, 22399572); based on our current understanding of frequencies and population sampling within studied cohorts, the potential impact of this haplotype on current case-control data is considered to be minor. Additional Reports of Patients with Deletions of This Region (including atypical or not identified by genomic CNV analysis): PMID: 21406098, 21815254, 21834050, 22929023, 23011633, 23495222, 23696316, 23165946

Triplosensitivity (TS) Score Details

TS Score:
2
TS Evidence Strength:
Emerging Evidence for Triplosensitivity (Disclaimer)
TS Published Evidence:
  • PUBMED: 26097203
    Barber et al. (2015) reviewed and summarized phenotypes of a total cohort of 17 probands with 8p23.1 recurrent duplication (originally reported in Barber et al. 2013, Yu et al. 2011, Barber et al. 2010, Yu et al. 2010, Barber et al. 2008, and Barber et al. 2005), 10 of which were characterized by genome-wide microarrays. Most frequent features summarized in the typical recurrent (full) duplication cohort included developmental delay (14/16 individuals), learning difficulties (9/14), variable dysmorphic features (10/17) and congenital heart disease (6/17). Additional variable phenotypes in at least 2 individuals included ADHD, neurological defects, hypotonia, seizures/EEG abnormalities, cleft lip/palate or high palate and ocular anomalies. Inheritance data from the 17 total probands was summarized in a prior review (Barber et al, 2013; PMID: 23345203) and showed the recurrent 8p23.1 duplication was de novo in 10, maternally or paternally transmitted in 4, and of unknown inheritance in 3 individuals. Of the 2 cases with parental transmission that were molecularly characterized, one carrier mother presented mild dysmorphic features and the other presented aortic stenosis and learning disability. This study also described novel atypical 8p23.1 duplications ranging from 187 to 4016 kb in size for genotype-phenotype correlation study.
  • PUBMED: 21933911
    Yu et al. (2011) reported 4 probands with recurrent 8p23.1 duplications identified by clinical array CGH. Clinical features in this cohort included developmental delay, dysmorphic features, neurodevelopmental problems, and various isolated findings. None of the probands had cardiac abnormalities. Inheritance of the duplication was de novo for 2 cases, maternal for 1 case (mother with history of learning disability and aortic stenosis), and unknown for the other. See also Yu et al. (2010) PMID 20461109, which included clinical summaries for three of these individuals.
  • PUBMED: 23165946
    Longoni et al. (2012) analyzed a cohort of individuals with congenital diaphragmatic hernias using aCGH identified individuals with copy number variants involving 8p23.1. One individual had the recurrent 8p23.1 duplication (inheritance unknown) with macrocephaly, expressive language delay and motor skill delay.
TS Evidence Comments:
NOTE (Jan 2023): following reevaluation of the duplication in June 2022 that resulted in a downgrade from a historical 3 score, a re-review occurred to determine whether a 2 or 3 score should be assigned, with the 2 score ultimately affirmed by the committee based on both expert consensus as well as evidence re-scoring through the metric. A modified summary is provided below to reflect additional nuances discussed since the update performed in June 2022. Evidence in support of the pathogenicity of recurrent 8p23.1 duplication is emerging at this time. A total of 10 individuals with the recurrent 8p23.1 duplication characterized by genome-wide microarrays can be considered for triplosensitivity scoring (17 total probands are described in the literature, with earlier cases characterized by chromosomes, FISH and lower resolution/targeted methods). Amongst these 10 cases, clinical findings observed in more than 3 patients include developmental delay/intellectual disability (7/10), dysmorphic features (4/10), congenital heart disease (3/10), and other findings. While duplications of the 8p23.1 region are generally rare in the literature, additional cases with overlapping features are also present in clinical databases. The recurrent 8p23.1 duplication has been reported in the literature to occur de novo in 4 out of 10 cases characterized by genome-wide microarrays (10 de novo cases out of the 17 total reported cases). There are 2 cases of documented parental (maternal) inheritance characterized by arrays (without additional pathogenic CNVs) with phenotypes that may be considered to be affected/mildly affected. Case-control studies, where performed, have a limited overall number of cases but support enrichment of this duplication in the clinical population. Of note, the recurrent 8p23.1 duplication appears to be absent in individuals in the general population from studies of natural genomic variation. Therefore, the triplosensitivity score is 2. Additional clinical reports and supportive case-control data are required to definitively assign this duplication a 3 score. Additional literature is summarized below: Case-Control Studies: PMID: 25217958 Coe et al. (2014) performed a large-scale case-control comparison study of the relative prevalence of CNVs in children with developmental delay/intellectual disability, multiple congenital anomalies, and other developmental phenotypes compared to controls. Duplications of the 8p23.1 region were observed in 6/29,085 cases versus 0/19,584 controls (p=0.0455; LR: Inf, 95% CI: 1-Inf), demonstrating nominal enrichment of this CNV in the clinical population. See also Cooper et al. (2011) PMID 21841781, which used an overlapping (older) dataset. Predisposing Haplotype Studies: Additionally, there is a predisposing haplotype for genomic rearrangements in 8p23.1 that has variable frequency across different human populations (see PMIDs 27803192, 22399572); based on our current understanding of frequencies and population sampling within studied cohorts, the potential impact of this haplotype on current case-control data is considered to be minor. Other Reports (atypical or not identified by genomic CNV analysis): PMIDs: 11746033, 12362038, 16077733, 17940555, 20167067

Genomic View

Select assembly: (NC_000008.10) ()