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  • individuals with variants in the

    2021-12-06

    13 individuals with variants in the codon 1031–1159 region had global developmental delay and apparent ID, ranging from speech delay and learning difficulties to markedly impaired basic life functions (Table 2 and Table S3). The last available occipitofrontal-circumference measurements revealed microcephaly (ranging from −2.8 to −5 standard deviations [SDs]) in 46% (6/13) of individuals. Cerebral magnetic resonance imaging (MRI) had been performed in 10 out of 13 individuals, and seven of those 10 (70%) showed structural dormin anomalies, including cerebellar vermis hypoplasia (6/10), ventricular enlargement (3/10), cortical atrophy (2/10), brainstem atrophy (2/10), polymicrogyria (1/10), focal gliosis (1/10), delayed myelination (1/10), and corpus callosum hypoplasia (1/10). Neurological examination revealed hypotonia in 31% (4/13) of individuals. Only one individual was reported to have epilepsy. Seven individuals (54%) were reported to require feeding exclusively by gastrostomy tube. Among the 10 individuals who were examined by echocardiography, 70% (7/10) had abnormal results, 50% (5/10) had ventricular septal defects, 30% (3/10) had patent ductus arteriosus, 30% (3/10) had patent foramen ovale, 20% (2/10) had pulmonary hypertension, and 20% (2/10) had aortic coarctation. Abdominal ultrasound revealed anomalies in 70% (7/10) of individuals in which it was performed. Abnormal renal morphology, namely multicystic dysplastic kidney, hydronephrosis, a duplicate kidney, and/or a small kidney, was described in 60% (6/10) of individuals, and vesicoureteral reflux was also observed in 30% (3/10) of these individuals. Individual 15 presented with a large left-sided posterolateral congenital diaphragmatic hernia (Table S3). Hernias of the abdominal wall were also found in 23% (3/13) of individuals and included an umbilical hernia, an omphalocele, and an inguinal hernia. Three males (3/6; 50%) had external-genitalia anomalies, including microphallus, hypoplastic scrotum, and cryptorchidism, and two females (2/7; 29%) had a duplicated vagina and/or uterus. Other observed anomalies included dysplastic nails (8/13; 62%), cleft lip and palate (5/13; 38%), clinodactyly of the fifth finger (4/13; 31%), laryngotracheomalacia (3/13), accessory nipple (3/13; 23%), bilateral cutaneous syndactyly of the second and third toe (2/13; 15%), and anomalies of the lacrimal glands (1/13; 8%; see also below with regard to individuals 1 and 19). Four individuals (4/13; 31%) had visual impairment, and three (3/13; 23%) had hearing impairment. Hearing impairment was associated with inner-ear malformations in two cases. Recurrent infections, mainly respiratory and urinary-tract infections, affected three out of 13 (23%) individuals. Individual 9 died at 12 years of age in the context of multiple co-morbidities, including renal failure with acute fluid fluctuations, tracheostomy for severely obstructive laryngotracheomalacia, intermittent supraventricular tachycardia, arterial insufficiency, and polyendocrinopathy (insulin-dependent diabetes, adrenal insufficiency, and hypothyroidism). TRRAP-associated chromatin remodeling complexes are generally associated with gene activation, which is consistent with their HAT activity. Nevertheless, the NuA4 complex has been shown to have a gene-repression activity necessary for ESC pluripotency.31, 32 This gene-repression activity seems to be independent from its lysine acetyltransferase activity. To test the hypothesis that TRRAP variants alter gene expression, we obtained skin fibroblasts from two individuals, individual 1, with p.Leu805Phe, and individual 19, with p.Trp1866Cys and performed next-generation sequencing with technical replicates of RNA (i.e., separately prepared libraries from the same samples). The RNA library preparation and sequencing as well as bioinformatics analysis methods can be found in the Supplemental Data. We found that, in comparison to two typically developing individuals (controls), both individuals with TRRAP variants had remarkably different gene expression patterns (Figure S2A). Interestingly, most differentially expressed genes (DEGs) analyzed with DESeq2 were upregulated in affected individuals compared to controls (Figure S2B). Moreover, the individual with p.Leu805Phe had 619 DEGs; the Log2 fold change (Log2FC) was higher than 2 or lower than −2, and the p value was adjusted for 10% false discovery rate lower than 0.01 (padj) (Supplemental Data, Table S5).