Clinical and Pathological Features of FTDP-17 with MAPT p.K298_H299insQ Mutation.

BACKGROUND: MAPT is a causative gene in frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), a hereditary degenerative disease with various clinical manifestations, including progressive supranuclear palsy, corticobasal syndrome, Parkinson's disease, and frontotemporal dementia. OBJECTIVES: To analyze genetically, biochemically, and pathologically multiple members of two families who exhibited various phenotypes of the disease. METHODS: Genetic analysis included linkage analysis, homozygosity haplotyping, and exome sequencing. We conducted tau protein microtubule polymerization assay, heparin-induced tau aggregation, and western blotting with brain lysate from an autopsy case. We also evaluated abnormal tau aggregation by using anti-tau antibody and PM-PBB3. RESULTS: We identified a variant, c.896_897insACA, p.K298_H299insQ, in the MAPT gene of affected patients. Similar to previous reports, most patients presented with atypical parkinsonism. Biochemical analysis revealed that the mutant tau protein had a reduced ability to polymerize microtubules and formed abnormal fibrous aggregates. Pathological study revealed frontotemporal lobe atrophy, midbrain atrophy, depigmentation of the substantia nigra, and four-repeat tau-positive inclusions in the hippocampus, brainstem, and spinal cord neurons. The inclusion bodies also stained positively with PM-PBB3. CONCLUSIONS: This study confirmed that the insACA mutation caused FTDP-17. The affected patients showed symptoms resembling Parkinson's disease initially and symptoms of progressive supranuclear palsy later. Despite the initial clinical diagnosis of frontotemporal dementia in the autopsy case, the spread of lesions could explain the process of progressive supranuclear palsy. The study of more cases in the future will help clarify the common pathogenesis of MAPT mutations or specific pathogeneses of each mutation.

Heterozygous ZNHIT3 variants within the 17q12 recurrent deletion region are associated with Mayer-Rokitansky-Kuster Hauser (MRKH) syndrome.

The molecular basis of mullerian aplasia, also known as Mayer-Rokitansky-Kuster Hauser (MRKH) or congenital absence of the uterus and vagina, is largely unknown. We applied a multifaceted genetic approach to studying the pathogenesis of MRKH including exome sequencing of trios and duos, genome sequencing of families, qPCR, RT-PCR, and Sanger sequencing to detect intragenic deletions, insertions, splice variants, single nucleotide variants, and rearrangements in 132 persons with MRKH. We identified two heterozygous variants in ZNHIT3 localized to a commonly involved CNV region at chromosome 17q12 in two different families with MRKH. One is a frameshift, truncating variant that is predicted to interfere with steroid hormone binding of the LxxLL sequence of the C-terminal region. The second variant is a double missense/stopgain variant. Both variants impair protein expression in vitro. In addition, four more probands with MRKH harbored the stopgain variant without the nearby missense variant. In total, 6/132 (4.5%) of patients studied, including five with associated anomalies (type 2 MRKH), had ZNHIT3 variants that impair function in vitro. Our findings implicate ZNHIT3 as an important gene associated with MRKH within the 17q12 CNV region.

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.

Germline MYOF1::WNK4 and VPS25::MYOF1 Chimeras Generated by the Constitutional Translocation t(17;19)(q21;p13) in Two Siblings With Myelodysplastic Syndrome.

BACKGROUND/AIM: Constitutional chromosomal aberrations are rare in hematologic malignancies and their pathogenetic role is mostly poorly understood. We present a comprehensive molecular characterization of a novel constitutional chromosomal translocation found in two siblings - sisters - diagnosed with myelodysplastic syndrome (MDS). MATERIALS AND METHODS: Bone marrow and blood cells from the two patients were examined using G-banding, RNA sequencing, PCR, and Sanger sequencing. RESULTS: We identified a balanced t(17;19)(q21;p13) translocation in both siblings' bone marrow, blood cells, and phytohemagglutinin-stimulated lymphocytes. The translocation generated a MYO1F::WNK4 chimera on the der(19)t(17;19), encoding a chimeric serine/threonine kinase, and a VPS25::MYO1F on the der(17), potentially resulting in an aberrant VPS25 protein. CONCLUSION: The t(17;19)(q21;p13) translocation found in the two sisters probably predisposed them to myelodysplasia. How the MYO1F::WNK4 and/or VPS25::MYO1F chimeras, perhaps especially MYO1F::WNK4 that encodes a chimeric serine/threonine kinase, played a role in MDS pathogenesis, remains incompletely understood.

Multiple primary dermatofibrosarcoma protuberans tumors in a single patient with chromosomal microarray analysis: A case report and review.

Dermatofibrosarcoma protuberans (DFSP) is a cutaneous sarcoma with a high propensity for local invasion and recurrence. Although it is a rare event, the occurrence of multiple tumors in a single patient raises a diagnostic dilemma, as metastatic disease should be differentiated from multiple primary malignant events. In more than 90% of DFSP, a pathogenic t(17;22) translocation leads to the expression of COL1A1::PDGFB fusion transcripts. Karyotype analysis, fluorescence in situ hybridization, and RT-PCR can be useful ancillary studies in detecting this characteristic rearrangement, and sequencing of the fusion transcript can be used to support a clonal origin in metastatic and multifocal disease. However, previous reports have demonstrated variable sensitivity of these assays, in part due to the high sequence variability of the COL1A1::PDGFB fusion. Here, we report a patient who developed two distinct DFSP tumors over the course of 7 years. Chromosomal microarray analysis identified distinctive genomic alterations in the two tumors, supporting the occurrence of multiple primary malignant events.

Imaging flow cytometric detection of del(17p) in bone marrow and circulating plasma cells in multiple myeloma.

BACKGROUND: Detection of del(17p) in myeloma is generally performed by fluorescence in situ hybridization (FISH) on a slide with analysis of up to 200 nuclei. The small cell sample analyzed makes this a low precision test. We report the utility of an automated FISH method, called "immuno-flowFISH", to detect plasma cells with adverse prognostic risk del(17p) in bone marrow and blood samples of patients with myeloma. METHODS: Bone marrow (n = 31) and blood (n = 19) samples from 35 patients with myeloma were analyzed using immuno-flowFISH. Plasma cells were identified by CD38/CD138-immunophenotypic gating and assessed for the 17p locus and centromere of chromosome 17. Cells were acquired on an AMNIS ImageStreamX MkII imaging flow cytometer using INSPIRE software. RESULTS: Chromosome 17 abnormalities were identified in CD38/CD138-positive cells in bone marrow (6/31) and blood (4/19) samples when the percent plasma cell burden ranged from 0.03% to 100% of cells. Abnormalities could be identified in 14.5%-100% of plasma cells. CONCLUSIONS: The "immuno-flowFISH" imaging flow cytometric method could detect del(17p) in plasma cells in both bone marrow and blood samples of myeloma patients. This method was also able to detect gains and losses of chromosome 17, which are also of prognostic significance. The lowest levels of 0.009% (bone marrow) and 0.001% (blood) for chromosome 17 abnormalities was below the detection limit of current FISH method. This method offers potential as a new means of identifying these prognostically important chromosomal defects, even when only rare cells are present and for serial disease monitoring.

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.

Uncommon fundus presentation of Koolen-De Vries Syndrome in a young boy.

INTRODUCTION: Koleen-De Vries syndrome (KDVS) is a rare genetic condition characterized by typical facial features, intellectual disability, cardiac and renal diseases, and ophthalmic manifestations. The syndrome is known to be caused by a microdeletion in the 17q21.31 region, involving multiple genes, including the KANSL1 gene. CASE PRESENTATION: We present the case of a 9-year-old boy with no family history of ophthalmic syndromes. The patient exhibited bilateral hypopigmented iris and unilateral choroidal and retinal pigment epithelium (RPE) hypopigmentation. DISCUSSION: The presence of ophthalmic manifestations, such as bilateral hypopigmented iris and unilateral choroidal and RPE hypopigmentation, in a patient with KDVS adds to the clinical spectrum of this syndrome. Although the exact mechanism underlying these ocular findings is not yet fully understood, the microdeletion in the 17q21.31 region, which includes the KANSL1 gene, is likely to play a role. CONCLUSION: This case highlights the importance of considering ophthalmic manifestations in individuals diagnosed with Koleen-De Vries syndrome. Further research is needed to better understand the pathogenesis and clinical implications of these ocular findings.

[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.

Optical genome mapping analysis of a Chinese pedigree with a rare chromosome 17 paracentric inversion insertion / 中华医学遗传学杂志

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.