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| Intellectual disability - microarray and sequencing v3.1534 | ZBTB7A |
Konstantinos Varvagiannis gene: ZBTB7A was added gene: ZBTB7A was added to Intellectual disability. Sources: Literature,Other Mode of inheritance for gene: ZBTB7A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: ZBTB7A were set to 31645653; 34515416 Phenotypes for gene: ZBTB7A were set to Global developmental delay; Intellectual disability; Macrocephaly; Abnormality of the lymphatic system; Sleep apnea; Increased body weight; Autism; Persistence of hemoglobin F; Abnormal leukocyte count; Recurrent infections; Umbilical hernia Penetrance for gene: ZBTB7A were set to unknown Review for gene: ZBTB7A was set to AMBER Added comment: Monoallelic pathogenic ZBTB7A variants cause Macrocephaly, neurodevelopmental delay, lymphoid hyperplasia, and persistent fetal hemoglobin (#619769). ---- Ohishi et al (2020 - PMID: 31645653) described the phenotype of a 6y5m-old male harboring a heterozygous, de novo ZBTB7A missense variant. Features included macrocephaly, mild intellectual disability (tIQ 65) and sleep apnea. Available hemoglobin levels (in the 1st month) supported high Hb and HbF levels. Other features included PDA and an umbilical hernia. Initial investigations incl. karyotype and CMA were normal. The ZBTB7A variant (NM_015898.3:c.1152C>G / p.Cys384Tyr) was identified following trio WES with a list of additional findings (in suppl.) not explaining the phenotype. This SNV, confirmed by Sanger sequencing, was absent from public db with several in silico predictions in favor of a deleterious effect. ZBTB7A on 19p encodes zinc finger- and BTB domain-containing protein 7 (or Pokemon). The authors performed a review of 19p13.3 microdeletion cases supporting a minimum region of overlap spanning PIAS4, ZBTB7A and MAP2K2 and common features of DD and ID, macrocephaly with prominent forehead, sleep apnea. The authors argue that loss of ZBTB7A explains part of - but probably not all - features of 19p13.3 microdeletions. ZBTB7A is known to repress expression of HBG1 and HBG2 (γ-globin), with the few available HbF patient measurements in line with this role. Based on the structure of the protein, Cys384 (along with 3 other residues) forms a coordinate bond with the Zn+2 ion, this bond predicted to be disrupted by Tyr. Further they favor a dominant negative effect given that ZBTB7A protein is known to form dimer via interaction at the BTB domain [hetero (variant+wt) and homodimers (variant+variant) having compromised function]. To support this notion, 3 previously reported somatic variants within the zinc-finger domain have been shown to exert a dominant-negative effect (PMID cited: 26455326). ---- In a collaborative study, von der Lippe et al (2022 - PMID: 34515416) identified 12 additional individuals (from 10 families) harboring monoallelic ZBTB7A missense/pLoF variants most commonly as de novo events. The authors describe a consistent phenotype with motor (9/11) and speech delay (9/12), cognitive impairment/ID (12/12 - commonly mild, ranged from specific learning difficulties to severe ID), macrocephaly (>90%le in 11/12, >97% in 7/12), lymphoid hypertrophy of pharyngeal tissue/adenoid overgrowth (12/12), sleep apnea (9/12). Autistic features were observed in 7/12. Other phenotypes included frequent upper airway infections (10/11), weight above 97th percentile (7/11). HbF levels were elevated in 4/5 individuals with available measurements (range: 2.2% to 11.2% - ref. for subjects above 6m of age : <2% ). Other hematological issues were observed in few individuals (abn. monocyte/neutrophil counts in 3-4). Cardiovascular issues were reported in 4 (2 fam). 3 subjects had umbilical hernia. There was no common dysmorphic feature. Various initial investigations were normal or did not appear to explain the NDD phenotype and incl. standard karyotype, CMA, targeted testing for genes/disorders previously considered (PTEN, FMR1, NSD1, BWS and PWS methylation studies, CFTR, etc). One male had a maternally inherited chrX dup not thought to explain his complex phenotype, while another had a concurrent diagnosis of thalassemia. Individuals were investigated with singleton (or trio) WES. Of note some individuals were DDD study participants. 8 had de novo ZBTB7A variants, incl. one who harbored 2 de novo missense SNVs several residues apart. 2 sibs had inherited a fs variant from their affected parent. For the latter as well as for another subject parental samples were unavailable. There were no other variants of interest upon exome analysis. 5 different missense, 2 nonsense and 3 fs variants were identified with pLoF all predicted to lead to NMD. All variants were absent from gnomAD (pLI of 0.96, LOEUF 0.33 and missense Z-score of 4.04) which lists one individual with htz LoF, likely not an artifact. Given this individual (and the familial case) the authors discuss on the mild phenotype and/or eventual reduced penetrance or underdiagnosis of the disorder. There was no difference in severity between those with missense/truncating variants. ZBTB7A transcription factor (or pokemon or lymphoma/leukemia-related factor) is widely expressed. It is involved in several activities being among others required to block Notch signaling which in turn drives T-cell at the expense of B-cell development. Notch pathway activation has been demonstrated in Zbtba7 ko mouse models. Finally, the authors discuss the role of notch signaling in thymus and the nervous system, as well as that ZBTB7A up/down-regulation known to repress/increase respectively HbF expression (several refs in text). ---- MGI (1335091) for Zbtb7a : "Mice homozygous for a knock-out allele die around E16.5 due to anemia and exhibit a cell autonomous defect in early B cell development". (Phenotypes from nervous system not commented on). ---- Apart from OMIM (#619769), ZBTB7A is included in the DD panel of G2P (ZBTB7A-associated developmental disorder / monoallelic_autosomal / absent gene product / confidence limited) as well as among the primary ID genes in SysID. In PanelApp Australia the gene is incl. with green rating in the ID and Macrocephaly gene panels. ---- Consider inclusion with amber or green rating (several individuals/families/variants, highly consistent phenotype, overlap with 19p microdeletions || variant effect not studied, animal models supporting contribution of the gene to the phenotype though no data on associated NDD ones). Please also consider inclusion in other relevant panels (macrocephaly, lymphatic disorders, ASD, etc). Sources: Literature, Other |
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| Intellectual disability - microarray and sequencing v2.1062 | APC2 |
Konstantinos Varvagiannis gene: APC2 was added gene: APC2 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: APC2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: APC2 were set to 31585108; 25753423; 19759310; 22573669 Phenotypes for gene: APC2 were set to Global developmental delay; Intellectual disability; Seizures; Morphological abnormality of the central nervous system Penetrance for gene: APC2 were set to Complete Review for gene: APC2 was set to GREEN gene: APC2 was marked as current diagnostic Added comment: Probably 14 individuals from 9 families (8 consanguineous) with biallelic APC2 LoF variants have been reported. ID and brain abnormalities were features in all, although the presentation was quite different between sibs in the first report (PMID: 25753423 - mild/mod ID, ventriculomegaly and CC anomalies, macrocephaly with variable height, Sotos-like facial features) and 12 subsequently described patients (PMID: 31585108 - severe ID, P>A lissencephaly/CC anomalies/ventriculomegaly/paucity of white matter in (almost) all, gT-C/myoclonic seizures in 8/12 with onset 3m-6y, OFC in the low percentiles). In all cases relevant alternative diagnoses (eg. macrocephaly/overgrowth syndromes - 1st report, mutations in other lissencephaly genes, metabolic disorders - 2nd) were ruled out. APC2 encodes Adenomatous polyposis coli protein 2, expressed in the CNS. All variants reported to date were LoF (stopgain/frameshift/splicing) and were supported by parental-only studies. Mutations in the 1st report as well as 4/8 variants from the 2nd report localized within the last exon (NM_005883.2 / longest of >=3 isoforms), although the 2nd report did not observe obvious genotype-phenotype correlations. Despite a pLI of 1 in gnomAD, Lee et al. comment that heterozygous carriers did not have any noticeable phenotype. They further note that carriers were not examined by brain MRI, though. 27 heterozygous high-confidence variants appear in individuals in gnomAD. Finally as commented on, APC2 is not mutated in colon cancer. Animal models: Apc -/- mice displayed disrupted neuronal migration, with defects of lamination of cerebral cortex and cerebellum supporting the observed brain abnormalities. In addition Apc2-deficient mice also presented impaired learning and memory abilities. Extensive additional studies have shown Apc2 co-localization with microtubules affecting their stabilization, distribution along actin fibers (all supporting a role in cytoskeletal organization) and regulation of Rac1 (a Rho GTPase). Generation of Neuro2a cells demonstrated abnormal localization mainly in cell bodies of mutant hAPC2 proteins (due to frameshift in the last exon / deletion of the C-terminal part) - different from wt (neurites, growth cones, cell bodies). The first patient report also provided evidence for Apc2 being a downstream effector of Nsd1, with Nsd1 knockdown brains displaying impaired migration / laminar positioning of cortical neurons (similar to Apc2-/- model) and rescued by forced expression of Apc2. Relevant articles: PMIDs: 19759310 and 22573669 (Shintani et al. 2009 & 2012) [mouse model] PMID: 25753423 (Almuriekhi et al. 2015) [2 individuals + mouse model] PMID: 31585108 (Lee et al. 2019) [12 individuals from 8 families] ----- In OMIM, the APC2-related phenotype is ?Sotos syndrome 3 (MIM 617169 - AR). G2P does not have any associated phenotype for this gene. In SysID, APC2 belongs to the Current primary ID genes. APC2 is included in gene panels for ID offered by some diagnostic laboratories (eg. Radboudumc, GeneDx). ----- Overall, this gene could be considered for inclusion in the ID panel probably as green (>3 individuals/families/variants, highly specific pattern of lissencephaly in 12/14, mouse model supporting migration defects and impaired learning/memory) rather than amber (differences between the 1st and the other families reported as for the OFC and presence of lissencephaly). Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.468 | NSD1 | Louise Daugherty Source Victorian Clinical Genetics Services was added to NSD1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing | NSD1 | BRIDGE consortium edited their review of NSD1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing | NSD1 | BRIDGE consortium edited their review of NSD1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing | NSD1 | BRIDGE consortium reviewed NSD1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||