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| Clefting v4.110 | ATR | Arina Puzriakova Phenotypes for gene: ATR were changed from SECKEL SYNDROME 1; SCKL1 to Seckel syndrome 1, OMIM:210600 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clefting v4.110 | ATR | Arina Puzriakova Mode of inheritance for gene: ATR was changed from to BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clefting v2.15 | HYAL2 | Eleanor Williams Phenotypes for gene: HYAL2 were changed from Cleft lip and palate, cor triatriatum to cleft lip/palate MONDO:0016044; triatrial heart MONDO:0015450 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clefting v2.3 | HYAL2 |
Aleš Maver gene: HYAL2 was added gene: HYAL2 was added to Clefting. Sources: Literature Mode of inheritance for gene: HYAL2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: HYAL2 were set to 28081210 Phenotypes for gene: HYAL2 were set to Cleft lip and palate, cor triatriatum Penetrance for gene: HYAL2 were set to unknown Review for gene: HYAL2 was set to RED Added comment: This entry is based on finding of homozygous HYAL2 variants in two inbred families with cleft lip and palate (CLP). Five Amish individuals aged 4–16 years affected by a syndromic form of CLP were reported with a homozygous variant K148R variant in HYAL2 gene and two children aged 7 and 12 years from an extended consanguineous Arab family were reported with a homozygous P250L variant in HYAL2 gene. Reduced expression of the HYAL2 protein consequental to the two missense vairants was shown in functional assays (PMID:28081210). Study of Hyal2 knock-out mice has also shown underdeveloped central palate bones and absence/reduction of ethmoid bone. The entry is based on this single study, therefore currently leaving this at Red level of evidence. Sources: Literature |
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| Clefting v2.3 | KAT5 |
Konstantinos Varvagiannis gene: KAT5 was added gene: KAT5 was added to Clefting. Sources: Literature Mode of inheritance for gene: KAT5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: KAT5 were set to 32822602 Phenotypes for gene: KAT5 were set to Severe global developmental delay; Intellectual disability; Seizures; Microcephaly; Behavioral abnormality; Sleep disturbance; Morphological abnormality of the central nervous system; Short stature; Oral cleft; Abnormality of the face Mode of pathogenicity for gene: KAT5 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: KAT5 was set to AMBER Added comment: Humbert el al (2020 - PMID: 32822602) report 3 individuals with de novo missense KAT5 variants. Features included severe DD (3/3) and ID (2/2 - the 3rd was 18m on last examination), microcephaly (2/3), behavioral anomalies (3/3) including severe sleep disorder (3/3 - table S1 / night walking, sleep onset delay, excessive daytime sleepiness), seizures (3/3 - variable type and age of onset), brain MRI abnormalities (3/3 - CC, cerebellar atrophy each in 2 subjects, focal polymicrogyria in 1), various genitourinary anomalies (3/3). All had moderately short stature (-1.95 SD to -2.9SD). Cleft LP and submucous cleft P were observed in 2/3. Facial features included round face, flat profile, depressed nasal bridge, downturned corners of mouth and prognathism (each in at least 2 subjects). KAT5 encodes a lysine acetyltransferase involved in gene expression, DNA repair, chromatine remodeling, apoptosis and cell proliferation. It is part of the NuA4 histone acetyltransferase (HAT) complex also called TIP60/p400 (TIP60 being another name for KAT5). Regulation by histone acetylation is important for proper development. 3 missense KAT5 SNVs were identified, one within the chromobarrel domain (aa 7-65 / NM_006388.3) and 2 in the acetyl-CoA binding domain (aa 365-420). Following generation of K562 cells expressing either WT or variants, it was demonstrated that wt/mt KAT5 assemble normally into NuA4/TIP60 complexes. Histone acetyltransferase activity was however impaired for all variants, suggesting a partial loss of function mechanism. As Humbert et al comment, it is possible that KAT5 haploinsufficiency does not lead to a syndrome. Over 10 high-confidence LoF variants are listed in gnomAD. Heterozygous Kat5 ko mice have normal development, growth and fertility. Homozygous ko mice are embryonic lethal. In haploinsufficient mice, reduction of mRNA to 50% has been shown to be compensated at the protein level in adipose and/or other tissues (several studies cited). RNA-Seq in fibroblasts from 2 affected individuals revealed dysregulation of highly relevant genes (e.g. for neurodevelopment, circadian clock, etc). Mutations in KAT6A/B, encoding two other acetyltransferases cause neurodevelopmental disorders with features overlapping those observed in individuals with KAT5 variants (e.g. DD/ID, microcephaly, seizures, sleep disturbance, clefts, CC or genital anomalies). Consider inclusion in the ID and epilepsy panels with green rating as well as the gene panel for clefting with amber. Sources: Literature |
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| Clefting v1.25 | ISCA-37423-Gain |
Louise Daugherty Region: ISCA-37423-Gain was added Region: ISCA-37423-Gain was added to Clefting. Sources: ClinGen,Expert Review Green Mode of inheritance for Region: ISCA-37423-Gain was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for Region: ISCA-37423-Gain were set to 21933911; 23345203 Phenotypes for Region: ISCA-37423-Gain were set to Behavioral problems, cleft lip and/or palate, macrocephaly, and seizures were confirmed as additional features among the new patients, and novel features included neonatal respiratory distress, attention deficit hyperactivity disorder (ADHD), ocular anomalies, balance problems, hypotonia, and hydrocele.; mild to moderate developmental delay, intellectual disability, mild facial dysmorphism (incl. prominent forehead, arched eyebrows, broad nasal bridge, upturned nares, cleft lip and/or palate) and congenital cardiac anomalies (e.g., atrioventricular septal defect). Other reported features include macrocephaly, behavioral abnormalities (e.g., attention deficit disorder), seizures, hypotonia and ocular and digital anomalies (poly/syndactyly); congenital heart disease; 8p23.1 duplication syndrome |
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| Clefting | ATR | Arianna Tucci commented on ATR | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clefting | ATR | Arianna Tucci commented on ATR | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clefting | ATRX | Ellen McDonagh reviewed ATRX | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clefting | ATR | Ellen McDonagh reviewed ATR | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||