Anesthesia management for a child with the Koolen-de Vries syndrome: a case report.

BACKGROUND: The Koolen-de Vries syndrome (KdVS) is a relatively new rare disease caused by micro-deletion of 17q21.31 which was first reported by Koolen in 2006. Typical phenotypes for KdVS include hypotonia, developmental delay, moderate intellectual disability, and characteristic facial dysmorphism. Up to now, there was only one case report about anesthesia management of patient diagnosed KdVS. It was a 2-year-old girl who experienced an MRI exam under anesthesia. CASE PRESENTATION: We described a 21-month-old boy who planned to undergo an orchidopexy under general anesthesia diagnosed with KdVS. He had an intellectual disability, characteristic facial dysmorphism, tracheo/laryngomalacia, patent foramen ovale, and cryptorchidism related to KdVS. Due to the complex condition especially the presence of tracheo/laryngomalacia, we took some special measures, including reducing the amount of long-acting opioid, keeping the spontaneous breath, performing a caudal block, and applying the laryngeal mask. But the laryngeal mask was changed to an endotracheal tube because it failed to provide adequate ventilation. The boy experienced mild laryngeal spasm and hypoxia after extubation, but lateral position and etomidate eased his breathing problem and re-intubation was avoided. It is indicated that anesthesia management for patients with orphan disease is a real challenge for all anesthesia providers. CONCLUSIONS: The Koolen-de Vries syndrome is a relatively new orphan disease involving multiple systems. Keeping spontaneous breath, evaluating airway potency to anesthetics, applying endotracheal tube, and post-extubation lateral or prone position may be helpful for airway management for patient with hypotonia and tracheo/laryngomalacia. KdVS patient needs prolonged post-anesthesia monitoring and/or medication for airway complications.

Report of IRF2BP1 as a novel partner of RARA in variant acute promyelocytic leukemia.

IRF2BP1 breaked in the middle of exon 1 at the c.322 position and fused with RARA intron 2 which is located at 3717 bp upstream of its exon 3. The fusion produced a new intron by forming a paired splicing donor GT at 9 bp downstream of RARA breakpoint and acceptor AG at the 5' end of RARA exon 3. The IRF2BP1::RARA fusion gene leads a fusion transcript involving IRF2BP1 exon 1 and RARA exon 3, linked by a 9-bp fragment derived from RARA intron 2. The patient with IRF2BP1::RARA has same clinical features of APL.

A new blood DNA methylation signature for Koolen-de Vries syndrome: Classification of missense KANSL1 variants and comparison to fibroblast cells.

Pathogenic variants in KANSL1 and 17q21.31 microdeletions are causative of Koolen-de Vries syndrome (KdVS), a neurodevelopmental syndrome with characteristic facial dysmorphia. Our previous work has shown that syndromic conditions caused by pathogenic variants in epigenetic regulatory genes have identifiable patterns of DNA methylation (DNAm) change: DNAm signatures or episignatures. Given the role of KANSL1 in histone acetylation, we tested whether variants underlying KdVS are associated with a DNAm signature. We profiled whole-blood DNAm for 13 individuals with KANSL1 variants, four individuals with 17q21.31 microdeletions, and 21 typically developing individuals, using Illumina's Infinium EPIC array. In this study, we identified a robust DNAm signature of 456 significant CpG sites in 8 individuals with KdVS, a pattern independently validated in an additional 7 individuals with KdVS. We also demonstrate the diagnostic utility of the signature and classify two KANSL1 VUS as well as four variants in individuals with atypical clinical presentation. Lastly, we investigated tissue-specific DNAm changes in fibroblast cells from individuals with KdVS. Collectively, our findings contribute to the understanding of the epigenetic landscape related to KdVS and aid in the diagnosis and classification of variants in this structurally complex genomic region.

[Optical genome mapping analysis of a Chinese pedigree with a rare chromosome 17 paracentric inversion insertion].

OBJECTIVE: To carry out optical genome mapping (OGM) for a Chinese pedigree with a rare paracentric reverse insertion of chromosome 17. METHODS: A high-risk pregnant woman identified at the Prenatal Diagnosis Center of Hangzhou Women's Hospital in October 2021 and her family members were selected as the study subjects. Chromosome G banding analysis, fluorescence in situ hybridization (FISH), single nucleotide polymorphism array (SNP array) and OGM were applied to verify the balanced structural abnormality of chromosome 17 in the pedigree. RESULTS: Chromosomal karyotyping analysis and SNP array assay have identified a duplication of 17q23q25 in the fetus. Karyotyping analysis of the pregnant woman showed that the structure of chromosome 17 was abnormal, whilst SNP array has detected no abnormality. OGM revealed that the woman has carried a paracentric reverse insertion, which was confirmed by FISH. The karyotype of her husband was normal. CONCLUSION: The duplication of 17q23q25 in the fetus has derived from a paracentric reverse insertion of chromosome 17 in its mother. OGM has the advantage for delineating balanced chromosome structural abnormalities.

The clinical phenotype of Koolen-de Vries syndrome in Turkish patients and literature review.

Koolen-de Vries syndrome (KdVS) is a rare multisystemic disorder caused by a microdeletion on chromosome 17q21.31 including KANSL1 gene or intragenic pathogenic variants in KANSL1 gene. Here, we describe the clinical and genetic spectrum of eight Turkish children with KdVS due to a de novo 17q21.31 deletion, and report on several rare/new conditions. Eight patients from unrelated families aged between 17 months and 19 years enrolled in this study. All patients evaluated by a clinical geneticist, and the clinical diagnosis were confirmed by molecular karyotyping. KdVS patients had some common distinctive facial features. All patients had neuromotor retardation, and speech and language delay. Epilepsy, structural brain anomalies, ocular, ectodermal, and musculoskeletal findings, and friendly personality were remarkable in more than half of the patients. Hypertension, hypothyroidism, celiac disease, and postaxial polydactyly were among the rare/new conditions. Our study contributes to the clinical spectrum of patients with KdVS, while also provide a review by comparing them with previous cohort studies.

How a paternal uniparental isodisomy of chromosome 17 leads to autosomal recessive limb-girdle muscular dystrophy R3.

Uniparental isodisomy is a condition where both chromosomes of a pair are inherited from one parental homologue. If a deleterious variant is present on the duplicated chromosome, its homozygosity can reveal an autosomal recessive disorder in the offspring of a heterozygous carrier. Limb-girdle muscular dystrophy (LGMD) R3 is an autosomal recessive inherited disease that is associated with alpha-sarcoglycan gene (SGCA) variants. We report the first published case of LGMDR3 due to a homozygous variant in SGCA unmasked by uniparental isodisomy. The patient is an 8-year-old who experienced delayed motor milestones but normal cognitive development. He presented with muscle pain and elevated plasma creatine kinase. Sequencing of the SGCA gene showed a homozygous pathogenic variant. Parents were not related and only the father was heterozygous for the pathogenic variant. A chromosomal microarray revealed a complete chromosome 17 copy number neutral loss of heterozygosity encompassing SGCA, indicating paternal uniparental isodisomy.

A 1.1 Mb duplication CNV on chromosome 17 contributes to skeletal muscle development in Boer goats.

The Boer goat is one of the top meat breeds in modern animal husbandry and has attracted widespread attention for its unique growth performance. However, the genetic basis of muscle development in the Boer goat remains obscure. In this study, we identified specific structural variants in the Boer goat based on genome-wide selection signals and analyzed the basis of the molecular heredity of related candidate genes in muscle development. A total of 9 959 autosomal copy number variations (CNVs) were identified through selection signal analysis in 127 goat genomes. Specifically, we confirmed that the highest signal CNV (HSV) was a chromosomal arrangement containing an approximately 1.11 Mb (CHIR17: 60062304-61171840 bp) duplicated fragment inserted in reverse orientation and a 5 362 bp deleted region (CHIR17:60145940-60151302 bp) with overlapping genes (e.g., ARHGAP10, NR3C2, EDNRA, PRMT9, and TMEM184C). The homozygous duplicated HSV genotype (+/+) was found in 96% of Boer goats but was not detected in Eurasian goats and was only detected in 4% of indigenous African goats. The expression network of three candidate genes ( ARHGAP10, NR3C2, and EDNRA) regulating dose transcription was constructed by RNA sequencing. Results indicated that these genes were involved in the proliferation and differentiation of skeletal muscle satellite cells (SMSCs) and their overexpression significantly increased the expression of SAA3. The HSV of the Boer goat contributed to superior skeletal muscle growth via the dose effects of overlapping genes.

Repair of Protruding Bilateral Cleft Lip and Palate With Staged Premaxilla Setback Osteotomy, Cheiloplasty, and Palatoplasty in Trisomy 17p Patient: A Review of Syndromic Clinical Characteristic.

Chromosome 17 duplication is correlated with an increased risk of developmental delay, birth defects, and intellectual disability. Here, we reported a female patient with trisomy 17 on the whole short arm with bilateral complete cleft lip and palate (BCLP). This study will review the surgical strategies to reconstruct the protruding premaxillary segment, cleft lip, and palate in trisomy 17p patient.The patient had heterozygous pathogenic duplication of chromosomal region chr17:526-18777088 on almost the entire short arm of chromosome 17. Beside the commonly found features of trisomy 17p, the patient also presented with BCLP with a prominent premaxillary portion. Premaxillary setback surgery was first performed concomitantly with cheiloplasty. The ostectomy was performed posterior to the vomero-premaxillary suture (VPS). The premaxilla was firmly adhered to the lateral segment and the viability of philtral flap was not compromised. Two-flap palatoplasty with modified intravelar veloplasty (IVV) was performed 4 months after.Successful positioning of the premaxilla segment, satisfactory lip aesthetics, and vital palatal flap was obtained from premaxillary setback, primary cheiloplasty, and subsequent palatoplasty in our trisomy 17p patient presenting with BLCP. Postoperative premaxillary stability and patency of the philtral and palatal flap were achieved. Longer follow-up is needed to evaluate the long-term effects of our surgical techniques on inhibition of midfacial growth. However, the benefits that the patient received from the surgery in improving feeding capacity and facial appearance early in life outweigh the cost of possible maxillary retrusion.

Further expansion and confirmation of phenotype in rare loss of YWHAE gene distinct from Miller-Dieker syndrome.

Deletion of 17p13.3 has varying degrees of severity on brain development based on precise location and size of the deletion. The most severe phenotype is Miller-Dieker syndrome (MDS) which is characterized by lissencephaly, dysmorphic facial features, growth failure, developmental disability, and often early death. Haploinsufficiency of PAFAH1B1 is responsible for the characteristic lissencephaly in MDS. The precise role of YWHAE haploinsufficiency in MDS is unclear. Case reports are beginning to elucidate the phenotypes of individuals with 17p13.3 deletions that have deletion of YWHAE but do not include deletion of PAFAH1B1. Through our clinical genetics practice, we identified four individuals with 17p13.3 deletion that include YWHAE but not PAFAH1B1. These patients have a similar phenotype of dysmorphic facial features, developmental delay, and leukoencephalopathy. In a review of the literature, we identified 19 patients with 17p13.3 microdeletion sparing PAFAH1B1 but deleting YWHAE. Haploinsufficiency of YWHAE is associated with brain abnormalities including cystic changes. These individuals have high frequency of epilepsy, intellectual disability, and dysmorphic facial features including prominent forehead, epicanthal folds, and broad nasal root. We conclude that deletion of 17p13.3 excluding PAFAH1B1 but including YWHAE is associated with a consistent phenotype and should be considered a distinct condition from MDS.

Chromosome 17 translocation affects sperm morphology: Two case studies and literature review.

We present two cases of infertile males with teratozoospermia stemming from chromosome 17 translocation. The patients present karyotypes that have not been previously reported. Genes located on breakpoints (17p11.2, 9q31, and 11p15) were analysed to find the probable mechanism affecting sperm morphology. Our results suggest that ALKBH5, TOP3A, and LLGL1 interactions may be an underlying cause of abnormal sperm head morphology. Translocation of chromosome 17 occurred in conjunction with chromosome 9 and chromosome 11 translocation in the two cases, resulting in oligozoospermia and asthenozoospermia, respectively. These abnormal phenotypes may involve meiosis- and motility-related genes such as LDHC, DNHD1, UBQLN3, and NUP98. Translocation is thus a risk factor for sperm morphological abnormalities and motility deficiency. The interaction network of 22 genes on breakpoints suggests that they contribute to spermatogenesis as a group. In conclusion, this study highlighted the importance of investigating genes linked to sperm morphology, together with chromosome 17 translocation and reproductive risks. For patients interested in screening before a future pregnancy, we recommend preimplantation genetic diagnosis to reduce the risk of karyotypically unbalanced foetuses and birth defects.

Next-generation sequencing errors due to genetic variation in WRAP53 encoding TCAB1 on chromosome 17.

Next-generation sequencing (NGS) is a valuable tool, but has limitations in sequencing through repetitive runs of single nucleotides (homopolymers). Pathogenic germline variants in WRAP53 encoding telomere Cajal body protein 1 (TCAB1) are a known cause of dyskeratosis congenita. We identified a significant NGS error in WRAP53, c.1562dup, p.Ala522Glyfs*8 (rs755116516 G>-/GG/GGG) that did not validate by Sanger sequencing. This error occurs because rs755116516 G>-/GG/GGG (Chr17:7,606,714) is polymorphic, and variants at this site challenge the ability of NGS to accurately call the correct number of nucleotides in a homopolymer run. This was further complicated by the fact that chr17:7,606,721 (rs769202794) is multiallelic G>A, C, T, and that chr17:7,606,722 is also multiallelic (rs7640C>A/G/T and rs373064567C>delC). In addition to the expert interpretation of potentially clinically actionable variants, it recommended that all variants in regions of the genome with homopolymers be validated by Sanger sequencing before clinical action.

[Genetic diagnosis of a case of Smith-Magenis syndrome due to a rare small-scale deletion].

OBJECTIVE: To report on a case of Smith-Magenis syndrome (SMS) due to a rare small-scale deletion. METHODS: Muscle samples from the the third fetus was collected after the in Medical history and clinical data of the patient were collected. The child and his parents were subjected to chromosome karyotyping analysis, multiplex ligation-dependent probe amplification (MLPA) and copy number variation sequencing (CNV-seq). RESULTS: The child was found to have a normal karyotype. MLPA and CNV-seq detection showed that he has harbored a 1.22 Mb deletion and a 0.3 Mb duplication in the 17p11.2 region. Neither of his parents was found to have similar deletion or duplication. CONCLUSION: The child was diagnosed with SMS due to a rare 1.22 Mb deletion in the 17p11.2 region, which is among the smallest deletions associated with this syndrome.

Next-generation phenotyping contributing to the identification of a 4.7 kb deletion in KANSL1 causing Koolen-de Vries syndrome.

Next-generation phenotyping (NGP) is an application of advanced methods of computer vision on medical imaging data such as portrait photos of individuals with rare disorders. NGP on portraits results in gestalt scores that can be used for the selection of appropriate genetic tests, and for the interpretation of the molecular data. Here, we report on an exceptional case of a young girl that was presented at the age of 8 and 15 and enrolled in NGP diagnostics on the latter occasion. The girl had clinical features associated with Koolen-de Vries syndrome (KdVS) and a suggestive facial gestalt. However, chromosomal microarray (CMA), Sanger sequencing, multiplex ligation-dependent probe analysis (MLPA), and trio exome sequencing remained inconclusive. Based on the highly indicative gestalt score for KdVS, the decision was made to perform genome sequencing to also evaluate noncoding variants. This analysis revealed a 4.7 kb de novo deletion partially affecting intron 6 and exon 7 of the KANSL1 gene. This is the smallest reported structural variant to date for this phenotype. The case illustrates how NGP can be integrated into the iterative diagnostic process of test selection and interpretation of sequencing results.

Asthma 17q21 polymorphism and risk of COVID-19 in children: Correspondence.

This correspondence discusses on published article on asthma 17q21 polymorphism and risk of COVID-19 in children. The effect of other possible confounding factors are discussed.

Functional regulatory variants implicate distinct transcriptional networks in dementia.

Predicting the function of noncoding variation is a major challenge in modern genetics. In this study, we used massively parallel reporter assays to screen 5706 variants identified from genome-wide association studies for both Alzheimer's disease (AD) and progressive supranuclear palsy (PSP), identifying 320 functional regulatory variants (frVars) across 27 loci, including the complex 17q21.31 region. We identified and validated multiple risk loci using CRISPR interference or excision, including complement 4 (C4A) and APOC1 in AD and PLEKHM1 and KANSL1 in PSP. Functional variants disrupt transcription factor binding sites converging on enhancers with cell type-specific activity in PSP and AD, implicating a neuronal SP1-driven regulatory network in PSP pathogenesis. These analyses suggest that noncoding genetic risk is driven by common genetic variants through their aggregate activity on specific transcriptional programs.

A novel RARA-SNX15 fusion in PML-RARA-positive acute promyelocytic leukemia with t(11;17;15)(q13;q21.2;q24.1).

Acute promyelocytic leukemia (APL) is characterized by a series of retinoic acid receptor (RAR) fusion genes that lead to the dysregulation of RAR signaling and onset of APL. PML-RARA is the most common fusion generated from t(15;17)(q24;q21). In addition, the reciprocal fusion RARA-PML is present in over 80% of t(15;17) APL cases. The bcr3 types of RARA-PML and RARA-PLZF in particular are reciprocal fusions that contribute to leukemogenesis. Here, we report a variant APL case with t(11;17;15)(q13;q21.2;q24.1). Massive parallel sequencing of patient RNA detected the novel fusion transcripts RARA-SNX15 and SNX15-LINC02255 along with the bcr3 type of PML-RARA. Genetic analysis revealed that RARA-SNX15L is an in-frame fusion due to intron retention caused by RNA mis-splicing. RARA-SNX15L consisted mainly of SNX15 domains, including the Phox-homology domain, which has a critical role in protein-protein interactions among sorting nexins and with other partners. Co-immunoprecipitation analysis revealed that RARA-SNX15L is directly associated with SNX15 and with itself. Further studies are needed to evaluate the biological significance of RARA-SNX15L in APL. In conclusion, this is the first report of APL with a complex chromosomal rearrangement involving SNX15.