Novel SETBP1 D874V adjacent to the degron causes canonical schinzel-giedion syndrome: a case report and review of the literature.

Schinzel-Giedion syndrome (SGS) is a severe multisystem disorder characterized by distinctive facial features, profound intellectual disability, refractory epilepsy, cortical visual impairment, hearing loss, and various congenital anomalies. SGS is attributed to gain-of-function (GoF) variants in the SETBP1 gene, with reported variants causing canonical SGS located within a 12 bp hotspot region encoding SETBP1 residues aa868-871 (degron). Here, we describe a case of typical SGS caused by a novel heterozygous missense variant, D874V, adjacent to the degron. The female patient was diagnosed in the neonatal period and presented with characteristic facial phenotype (midface retraction, prominent forehead, and low-set ears), bilateral symmetrical talipes equinovarus, overlapping toes, and severe bilateral hydronephrosis accompanied by congenital heart disease, consistent with canonical SGS. This is the first report of a typical SGS caused by a, SETBP1 non-degron missense variant. This case expands the genetic spectrum of SGS and provides new insights into genotype-phenotype correlations.

Delayed Bone Age in a Child with a Novel Loss-of-Function Variant in SETBP1 Gene Sheds Light on the Potential Role of SETBP1 Protein in Skeletal Development.

Introduction: SETBP1 gene variants that decrease or eliminate protein activity have been associated with phenotypes characterized by speech apraxia and intellectual disabilities. This condition, distinctly separated from Schinzel-Giedion syndrome, is referred to as autosomal dominant mental retardation 29 (ADR29). Case Presentation: In this report, we present the case of a 6-year-old male patient exhibiting fine and global motor skill impairments along with expressive language delay. The patient carried a novel germline, heterozygous, de novo nonsense variant in the SETBP1 gene, specifically the c.532C>T variant, which prematurely terminates protein translation at amino acid 178, p.(Gln178*), and removes more than 10% of the reference protein isoform consisting of 1,596 amino acids. According to the American College of Medical Genetics and Genomics (ACMG) guidelines, this variant has been classified as pathogenic. Conclusion: Given the limited number of ADR29 cases reported to date, it is critical to focus attention on the phenotypic features of each new individual and seek out previously undocumented defects. The clinical findings found in our patient align with current knowledge on the correlation between the genotypes characterized by loss-of-function variants in SETBP1 gene and a particular neurological phenotype. Furthermore, the presence of a severely delayed bone age in this patient, which we report for the first time, could indicate a possible indirect but significant contribution of the SETBP1 protein in bone development and maturation processes. This finding highlights the need for further investigation into the potential effects of SETBP1 gene variants on bone health and the possible involvement of the SETBP1 protein in skeletal growth and development.

Cell-type-specific gene expression and regulation in the cerebral cortex and kidney of atypical Setbp1S858R Schinzel Giedion Syndrome mice.

Schinzel Giedion Syndrome (SGS) is an ultra-rare autosomal dominant Mendelian disease presenting with abnormalities spanning multiple organ systems. The most notable phenotypes involve severe developmental delay, progressive brain atrophy, and drug-resistant seizures. SGS is caused by spontaneous variants in SETBP1, which encodes for the epigenetic hub SETBP1 transcription factor (TF). SETBP1 variants causing classical SGS cluster at the degron, disrupting SETBP1 protein degradation and resulting in toxic accumulation, while those located outside cause milder atypical SGS. Due to the multisystem phenotype, we evaluated gene expression and regulatory programs altered in atypical SGS by snRNA-seq of the cerebral cortex and kidney of Setbp1S858R heterozygous mice (corresponds to the human likely pathogenic SETBP1S867R variant) compared to matched wild-type mice by constructing cell-type-specific regulatory networks. Setbp1 was differentially expressed in excitatory neurons, but known SETBP1 targets were differentially expressed and regulated in many cell types. Our findings suggest molecular drivers underlying neurodevelopmental phenotypes in classical SGS also drive atypical SGS, persist after birth, and are present in the kidney. Our results indicate SETBP1's role as an epigenetic hub leads to cell-type-specific differences in TF activity, gene targeting, and regulatory rewiring. This research provides a framework for investigating cell-type-specific variant impact on gene expression and regulation.

Trichorhinophalangeal syndrome type 1 (Giedion syndrome): A case report with literature review.

INTRODUCTION AND OBJECTIVES: Trichorhinophalangeal syndrome (TRPS) is a rare multisystem disorder characterized by abnormalities in the hair (tricho), nose (rhino), and digits (phalangeal). A variety of nonspecific intraoral findings have been reported in the literature, including hypodontia, delayed tooth eruption, malocclusion, a high-arched palate, mandibular retrognathia, midface hypoplasia, and multiple impacted teeth. In addition, supernumerary teeth have been detected in several persons with TRPS, especially type 1. This report describes the clinical manifestations and dental management of a TRPS 1 patient with multiple impacted supernumerary and permanent teeth. PATIENT: A 15-year-old female patient visited our clinic with a known medical history of TRPS 1 with laceration of the tongue caused by teeth eruption in the palate. RESULTS: Radiographic images showed a total of 45 teeth: two deciduous, 32 permanent, and 11 supernumerary teeth. Six permanent teeth and 11 supernumerary teeth in the posterior quadrants were impacted. Four impacted third molars, supernumerary teeth, retained deciduous teeth, and impacted maxillary premolars were removed under general anaesthesia. DISCUSSION AND CONCLUSIONS: This case suggests that all patients with TRPS should undergo full clinical and radiographic oral examination and should be informed about the disease and the importance of dental counselling.

Trichorhinophalangeal syndrome type 1 (Giedion syndrome): A case report with literature review / Síndrome tricorrinofalángico tipo 1 (síndrome de Giedion): caso clínico y revisión de la literatura

Introduction and objectives: Trichorhinophalangeal syndrome (TRPS) is a rare multisystem disorder characterized by abnormalities in the hair (tricho), nose (rhino), and digits (phalangeal). A variety of nonspecific intraoral findings have been reported in the literature, including hypodontia, delayed tooth eruption, malocclusion, a high-arched palate, mandibular retrognathia, midface hypoplasia, and multiple impacted teeth. In addition, supernumerary teeth have been detected in several persons with TRPS, especially type 1. This report describes the clinical manifestations and dental management of a TRPS 1 patient with multiple impacted supernumerary and permanent teeth. Patient: A 15-year-old female patient visited our clinic with a known medical history of TRPS 1 with laceration of the tongue caused by teeth eruption in the palate. Results: Radiographic images showed a total of 45 teeth: two deciduous, 32 permanent, and 11 supernumerary teeth. Six permanent teeth and 11 supernumerary teeth in the posterior quadrants were impacted. Four impacted third molars, supernumerary teeth, retained deciduous teeth, and impacted maxillary premolars were removed under general anaesthesia. Discussion and conclusions: This case suggests that all patients with TRPS should undergo full clinical and radiographic oral examination and should be informed about the disease and the importance of dental counselling.(AU)

Introducción y objetivos: El síndrome tricorrinofalángico (TRPS) es un trastorno multisistémico raro caracterizado por anomalías en el pelo (trico), la nariz (rino) y los dedos (falángico). En la literatura se han reportado una variedad de hallazgos intraorales inespecíficos, incluyendo hipodontia, demora de la erupción dental, maloclusión, paladar muy arqueado, retrognatia mandibular, hipoplasia en la sección media del rostro y múltiples dientes impactados. Además, se han detectado dientes supernumerarios en diversas personas con TRPS, en especial de tipo 1. Este informe describe las manifestaciones clínicas y el manejo dental de una paciente con TRPS 1 con múltiples dientes impactados, supernumerarios y permanentes. Paciente: Una paciente de 15 años con historia médica conocida de TRPS 1 se presentó en nuestra clínica quejándose de laceración de la lengua causada por dientes erupcionados. Resultados: Las imágenes radiográficas mostraron un total de 45 dientes: 2 deciduos, 32 permanentes y 11 supernumerarios. Seis dientes permanentes y 11 dientes supernumerarios de los cuadrantes posteriores resultaron impactados. Se extrajeron 4 terceros molares y dientes supernumerarios impactados, dientes deciduos retenidos y premolares maxilares impactados bajo anestesia general. Discusión y conclusiones. Este caso evidencia que todos los pacientes con TRPS deberían someterse a exámenes orales completos a nivel clínico y radiográfico, y ser informados sobre la enfermedad y la importancia del asesoramiento dental.(AU)

Detection of a novel SETBP1 variant in a Chinese neonate with Schinzel-Giedion syndrome.

Schinzel-Giedion syndrome (SGS) is a multiple malformation syndrome characterized by typical facial features, severe neurodevelopmental delay, and multiple congenital abnormalities. SGS is associated with de novo pathogenic variants in the SETBP1 gene. In specific, SETBP1 variants in over 50 patients with classical or non-classical SGS were clustered within exon 4. A male Chinese neonate with dysmorphic facial features, nervous system disorders, and organ malformations at birth was examined in this study and long-term followed-up. Whole-exome sequencing was performed to identify any underlying pathogenic variants in the proband. Additionally, we reviewed the literature that documents the main clinical features and underlying variants of all patients genetically diagnosed with SGS. The neonate had a characteristic midface retraction, abnormal electroencephalogram waveforms, and genital abnormalities. The patient did not initially develop hydronephrosis or undergo a comprehensive skeletal assessment. Six months after birth, the patient had an epileptic seizure and experienced persistent neurodevelopmental delay with auditory and visual abnormalities. Color Doppler ultrasonography at 18 months revealed hydronephrosis and bilateral widening of the lateral ventricles. The patient died suddenly 20.5 months after birth. Whole-exome sequencing revealed a heterozygous de novo variant (c.2605A > G:p.S869G) in exon 4 degradation sequence in SETBP1. The reported de novo heterozygous variant in SETBP1 (c.2605A > G:p.S869G) broadens the knowledge of the scientific community's on the possible SGS genetic alterations. To the best of our knowledge, this is the first report of SETBP1 variant (c.2605A > G:p.S869G) in SGS. The clinical manifestations of neonatal SGS are atypical, and genetic testing is crucial for diagnosis. Long-term follow-up should be conducted after diagnosis to optimize the therapeutic interventions.

Putative Roles of SETBP1 Dosage on the SET Oncogene to Affect Brain Development.

Mutations in SET BINDING PROTEIN 1 (SETBP1) cause two different clinically distinguishable diseases called Schinzel-Giedion syndrome (SGS) or SETBP1 deficiency syndrome (SDD). Both disorders are disorders of protein dosage, where SGS is caused by decreased rate of protein breakdown due to mutations in a proteosome targeting domain, and SDD is caused by heterozygous loss-of-function mutations leading to haploinsufficiency. While phenotypes of affected individuals support a role for SETBP1 in brain development, little is known about the mechanisms that might underlie this. The binding partner which gave SETBP1 its name is SET and there is extensive literature on this important oncogene in non-neural tissues. Here we describe different molecular complexes in which SET is involved as well as the role of these complexes in brain development. Based on this information, we postulate how SETBP1 protein dosage might influence these SET-containing molecular pathways and affect brain development. We examine the roles of SET and SETBP1 in acetylation inhibition, phosphatase activity, DNA repair, and cell cycle control. This work provides testable hypotheses for how altered SETBP1 protein dosage affects brain development.

Minimal Critical Region and Genes for a Typical Presentation of Langer-Giedion Syndrome.

Langer-Giedion syndrome (LGS) is caused by a contiguous deletion at 8q23q24, characterized by exostoses, facial, ectodermal, and skeletal anomalies, and, occasionally, intellectual disability. LGS patients have been diagnosed clinically or by routine cytogenetic techniques, hampering the definition of an accurate genotype-phenotype correlation for the syndrome. We report two unrelated patients with 8q23q24 deletions, characterized by cytogenomic techniques, with one of them, to our knowledge, carrying the smallest deletion reported in classic LGS cases. We assessed the pathogenicity of the deletion of genes within the 8q23q24 region and reviewed other molecularly confirmed cases from the literature. Our findings suggest a 3.2-Mb critical region for a typical presentation of the syndrome, emphasizing the contribution of the TRPS1, RAD21, and EXT1 genes' haploinsufficiency, and facial dysmorphisms as well as bone anomalies as the most frequent features among patients with LGS. We also suggest a possible role for the CSMD3 gene, whose deletion seems to contribute to central nervous system anomalies. Since studies performing such correlation for LGS patients are limited, our data contribute to improving the ge-notype-phenotype characterization for LGS patients.

A pathogenic variant in the SETBP1 hotspot results in a forme-fruste Schinzel-Giedion syndrome.

Schinzel-Giedion syndrome (SGS; OMIM 269150) is an ultra-rare genetic disorder associated with a distinctive facial gestalt, congenital malformations, severe intellectual disability, and a progressive neurological course. The prognosis for SGS is poor, with survival beyond the first decade rare. Germline, de novo heterozygous variants in the SETBP1 gene cause SGS with the pathogenic variants associated with the SGS phenotype missense and confined to exon 4 of the gene, clustered in a four amino acid (12 bp) hotspot in the SKI homologous region of the SETBP1 protein. We report a patient with a de novo I871S variant within the SKI homologous region, which has been associated with the severe phenotype previously; but our patient has fewer features of SGS and a milder course. This is the first report of a forme-fruste phenotype in a patient with a pathogenic variant within the SGS hotspot on the SETBP1 gene and it highlights the importance of considering atypical clinical presentations in the context of severe ultra-rare genetic disorders.

The recurrent SETBP1 c.2608G > A, p.(Gly870Ser) variant in a patient with Schinzel-Giedion syndrome: an illustrative case of the utility of whole exome sequencing in a critically ill neonate.

BACKGROUND: Schinzel-Giedion syndrome (SGS) is a multiple malformation syndrome mainly characterized by severe intellectual disability, distinctive facial features, and multiple congenital anomalies, including skeletal abnormalities, genitourinary and renal malformations, cardiac defects, as well as an increased pediatric cancer risk. Recently, SGS has been associated with de novo heterozygous deleterious variants in the SETBP1 gene; to date, nine different variants, clustering in exon 4 of SETBP1, have been identified in 25 patients. CASE PRESENTATION: In this study, by using Whole Exome Sequencing (WES), we identified a patient with a recurrent missense mutation in SETBP1, the c.2608G > A, p.(Gly870Ser) variant, previously reported as likely pathogenic. This finding allowed us to confirm the suspected clinical diagnosis of SGS. Clinical features of patients carrying the same variant, including our patient, were evaluated by a review of medical records. CONCLUSIONS: Our study confirms SGS as a severe disorder potentially presenting at birth as a critically ill neonate and demonstrates the causal role of the c.2608G > A, p.(Gly870Ser) variant in the etiology of the syndrome. Moreover, although the cohort of SETBP1-patients reported in the literature is still small, our study reports for the first time the prevalence of the variant (about 27%, 7/26). Finally, given the heterogeneity of clinical presentations of affected patients hospitalized in Neonatal Intensive Care Units (NICU) and/or Pediatric Intensive Care Units (PICU), in agreement with emerging data from the literature, we suggest that WES should be used in the diagnosis of unexplained syndromic conditions, and even as part of a standard first-line diagnostic approach, as it would allow a better diagnosis, counseling and management of affected patients and their families.

Mixed Phenotype of Langer-Giedion's and Cornelia de Lange's Syndromes in an 8q23.3-q24.1 Microdeletion without TRPS1 Deletion.

Langer-Giedion's syndrome (LGS) or trichorhinophalangeal syndrome type II (TRPS II; MIM:150230) is a contiguous gene deletion syndrome caused by the haploinsufficiency of the TRPS1 and EXT1 genes. Cornelia de Lange's syndrome (CdLS) is a genetically heterogeneous dysmorphic syndrome where heterozygous mutations of RAD21 gene have been associated with a mild clinical presentation (CDLS type 4; MIM: 614701). We report a female patient with a 2.3-Mb interstitial deletion at 8q23.3-q24.1 encompassing EXT1 and RAD21 genes but not TRPS1 . Clinical findings in this patient are correlated with a mixed phenotype of LGS and CdLS type 4.

Langer-Giedion Syndrome with 8q23.1–q24.13 Deletion by Complex Three-way Translocation

Langer-Giedion syndrome is a very rare genetic disorder that is caused by the deletion on chromosome 8q24.1, encompassing the TRPS1 and EXT1 genes. We describe a 5-month-old female patient who was admitted to our hospital with clinodactyly and weakness in both thumbs. The patient's karyotype was 46,XX,der(4)t(4;19)(q27;q11),der(8)t(4;8)(q27;q22.3),der(19)t(8;19)(q22.3;q11)del(8)(q23q24.1). Multiplex ligation-dependent probe amplification (MLPA) analysis showed that the patient had a heterozygous deletion, rsa 8q24(P064)x1 and rsa 8q24(P245)x1. Array comparative genomic hybridization (CGH) analysis further revealed three interstitial deletions spanning a total of 13.7 Mb at 8q23.1–q24.13. Based on clinical findings and confirmation by cytogenetic, MLPA, and array CGH analyses, the patient was diagnosed with sporadic Langer-Giedion syndrome with three-way translocations. This is the first case of Langer-Giedion syndrome with complex chromosomal rearrangements in Korea.

SETBP1 dysregulation in congenital disorders and myeloid neoplasms.

Myeloid malignancies are characterized by an extreme molecular heterogeneity, and many efforts have been made in the past decades to clarify the mechanisms underlying their pathogenesis. In this scenario SET binding protein 1 (SETBP1) has attracted a lot of interest as a new oncogene and potential marker, in addition to its involvement in the Schinzel-Giedon syndrome (SGS). Our review starts with the analysis of the structural characteristics of SETBP1, and extends to its corresponding physiological and pathological functions. Next, we describe the prevalence of SETBP1 mutations in congenital diseases and in hematologic malignancies, exploring how its alterations might contribute to tumor development and provoke clinical effects. Finally, we consider to understand how SETBP1 activation could be exploited in molecular medicine to enhance the cure rate.

Multiple long bone cysts revealed by MRI in trichorhinophalangeal syndrome type II predisposing to pathological fractures.

Trichorhinophalangeal syndrome type II is a rare genetic disorder with the few published case reports mainly reporting the radiographic skeletal manifestations. There are no published imaging reports of long bone cysts involving multiple bones in this condition. We report a unique case of bone cysts involving multiple long bones detected with MRI in a patient with trichorhinophalangeal syndrome type II complicated by a subsequent pathological fracture. It is possible that the bone cysts are a previously undescribed feature of this syndrome; however, the evidence is insufficient to establish a definite association. Chromosomal abnormality identified in this patient is consistent with trichorhinophalangeal syndrome type II with no unusual features. Although the nature of these bone cysts is unclear, they are one of the causes of the known increased fracture risk observed in this syndrome.

Genetic and prenatal findings in two Japanese patients with Schinzel-Giedion syndrome.

We report two Japanese patients with Schinzel-Giedion syndrome. When polyhydramnios is observed, additional fetal findings such as overlapping fingers, hydrocephalus, hydronephrosis, and very characteristic facial appearance comprising high, prominent forehead, hypertelorism, and depressed nasal root may suggest Schinzel-Giedion syndrome.

Making extra teeth: Lessons from a TRPS1 mutation.

A Thai mother and her two daughters were affected with tricho-rhino-phalangeal syndrome type I. The daughters had 15 and 18 supernumerary teeth, respectively. The mother had normal dentition. Mutation analysis of TRPS1 showed a novel heterozygous c.3809_3811delACTinsCATGTTGTG mutation in all. This mutation is predicted to cause amino acid changes in the Ikaros-like zinc finger domain near the C-terminal end of TRPS1, which is important for repressive protein function. The results of our study and the comprehensive review of the literature show that pathways of forming supernumerary teeth appear to involve APC and RUNX2, the genes responsible for familial adenomatous polyposis syndrome and cleidocranial dysplasia, respectively. The final pathway resulting in supernumerary teeth seems to involve Wnt, a morphogen active during many stages of development. © 2016 Wiley Periodicals, Inc.

Langer-Giedion Syndrome: a Rare Case Report.

Langer-Giedion syndrome is a very uncommon autosomal dominant genetic disorder caused by the deletion of chromosomal material. It is characterized by multiple bony exostosis, short stature, mental retardation, and typical facial features. The characteristic appearance of individuals includes sparse scalp hair, rounded nose, prominent philtral area and thin upper lip. Some cases with this condition have loose skin in childhood which typically resolves with age. Oral and dental manifestations include micrognathia, retrognathia, hypodontia, and malocclusion based on cephalometric analysis. This report presents a case of Langer-Giedion syndrome in a 10-year-old child.

Síndrome de Langer-Giedion con deleción 8q23. 1-q24. 12, diagnosticado por hibridación genómica comparativa / Langer-Giedion syndrome with 8q23. 1-q24. 12 deletion diagnosed by comparative genomic hybridization

El síndrome de Langer-Giedion, también conocido como síndrome tricorrinofalángico tipo II, es una enfermedad hereditaria multisistémica que pertenece al grupo de síndromes por deleción de genes contiguos. La causa de este síndrome es una deleción heterocigota que compromete, por lo general, la región 8q23.3-q24.11 y afecta, principalmente, los genes TRPS1, RAD21 y EXT1. Este síndrome se caracteriza por osteocondromatosis múltiple en las extremidades, hipertricosis y fenotipo facial, que incluye pelo escaso en el cuero cabelludo, orejas grandes sobresalientes y nariz larga con una punta bulbosa. Se reporta el caso de un paciente colombiano con hallazgo de deleción en la región cromosómica 8q23.1-q24.12 mediante técnicas de hibridación genómica comparativa y hallazgos clínicos clásicos. Este es el primer caso reportado en Colombia.

The Langer-Giedion syndrome, also known as trichorhinophalangeal syndrome type II, is a hereditary multisystemic disease part of the group of contiguous gene deletion syndromes. The cause of this syndrome is a heterozygous deletion that involves the chromosomal region 8q23.3-q24.11 and mainly affects genes TRPS1, RAD21, and EXT1. This syndrome is characterized by the presence of multiple osteochondromas in limbs, hypertrichosis, and facial phenotype that includes sparse scalp hair, large laterally protruding ears, a long nose with a bulbous tip. We report the case of a Colombian patient with finding of an 8q23.1-q24.12 deletion by comparative genomic hybridization array technique and classical clinical findings, being the first case reported in Colombia.

[Langer-Giedion syndrome with 8q23.1-q24.12 deletion diagnosed by comparative genomic hybridization]. / Síndrome de Langer-Giedion con deleción 8q23.1-q24.12, diagnosticado por hibridación genómica comparativa.

The Langer-Giedion syndrome, also known as trichorhinophalangeal syndrome type II, is a hereditary multisystemic disease part of the group of contiguous gene deletion syndromes. The cause of this syndrome is a heterozygous deletion that involves the chromosomal region 8q23.3-q24.11 and mainly affects genes TRPS1, RAD21, and EXT1. This syndrome is characterized by the presence of multiple osteochondromas in limbs, hypertrichosis, and facial phenotype that includes sparse scalp hair, large laterally protruding ears, a long nose with a bulbous tip. We report the case of a Colombian patient with finding of an 8q23.1-q24.12 deletion by comparative genomic hybridization array technique and classical clinical findings, being the first case reported in Colombia.

El síndrome de Langer-Giedion, también conocido como síndrome tricorrinofalángico tipo II, es una enfermedad hereditaria multisistémica que pertenece al grupo de síndromes por deleción de genes contiguos. La causa de este síndrome es una deleción heterocigota que compromete, por lo general, la región 8q23.3-q24.11 y afecta, principalmente, los genes TRPS1, RAD21 y EXT1. Este síndrome se caracteriza por osteocondromatosis múltiple en las extremidades, hipertricosis y fenotipo facial, que incluye pelo escaso en el cuero cabelludo, orejas grandes sobresalientes y nariz larga con una punta bulbosa. Se reporta el caso de un paciente colombiano con hallazgo de deleción en la región cromosómica 8q23.1-q24.12 mediante técnicas de hibridación genómica comparativa y hallazgos clínicos clásicos. Este es el primer caso reportado en Colombia.

Prenatal diagnosis and array comparative genomic hybridization characterization of interstitial deletions of 8q23.3-q24.11 and 8q24.13 associated with Langer-Giedion syndrome, Cornelia de Lange syndrome and haploinsufficiency of TRPS1, RAD21 and EXT1.

OBJECTIVE: The aim of this research was to present prenatal diagnosis of Langer-Giedion syndrome (LGS/TRPS type II) and Cornelia de Lange syndrome-4 (CDLS4). MATERIALS AND METHODS: A 36-year-old woman underwent amniocentesis at 17 weeks of gestation because of advanced maternal age. Conventional cytogenetic analysis of amniocentesis revealed an interstitial deletion of chromosome 8q or del(8)(q23.3q24.13). Level II prenatal ultrasound examination revealed craniofacial dysmorphism. The pregnancy was terminated, and a malformed fetus was delivered with characteristic craniofacial dysmorphism of LGS/TRPS type II and CDLS4. Whole-genome array comparative genomic hybridization (aCGH) on the DNA extracted from cultured amniocytes was performed. RESULTS: The analysis by aCGH revealed a result of arr 8q23.3q24.11 (116,087,006-118,969,399)×1, 8q24.13 (123,086,851-124,470,847)×1 (NCBI build 37) with a 2.88-Mb deletion of 8q23.3-q24.11 encompassing six OMIM genes, TRPS1, EIF3H, RAD21, SLC30A8, MED30, and EXT1, and a 1.383-Mb deletion of 8q24.13 encompassing four OMIM genes, ZHX2, DERL1, ZHX1, and ATAD2. CONCLUSION: In the present case, the conventional cytogenetic analysis of cultured amniocytes revealed del(8)(q23.3q24.13), whereas aCGH analysis of cultured amniocytes showed the deletions of 8q23.3-q24.11 and 8q24.13 with the presence of the segment 8q24.12. Therefore, aCGH provides the advantage of better understanding of the nature of interstitial deletion and genotype-phenotype correlation in this case.