What is all autosomal whole region partial deletion/duplication syndrome?

We studied a family with individuals exhibiting trisomy phenotypes, where the same 10 Mb inverted duplication of 2p25.3-p25.1 segregates in two children and their father. As the duplication was demonstrated to be inverted by FISH analysis, it was speculated that contiguous terminal deletions may also be present following the classical inv dup del rearrangement. FISH using 2p and 2q subtelomere probes yielded normal results, but array CGH (aCGH) at 100 kb resolution showed a 273 kb deletion in addition to the duplication. Although only one informative spot with normal log ratio was detected, high-resolution aCGH analysis (~20 kb) further suggested the presence of a single-copy region between the deletion and duplication regions. The precise structure of the rearrangement was redefined by real-time PCR and breakpoint cloning, demonstrating the presence of a 2680 bp single-copy sequence between the deletion and duplication regions and implicating simple repeats that could form non-B DNA structures. This rearrangement may not have been mediated by segmental duplications or short inverted repeats, and double-strand breaks may have been repaired by nonhomologous end joining or microhomology-mediated end-joining repair. These data emphasize that accompanying deletions associated with inversions may occur much more frequently than can be demonstrated by classical cytogenetic methods alone. We discuss the impact on trisomy and 2p terminal deletion phenotypes.

We report on a 4.8-year-old boy confirmed with severe growth retardation, growth hormone (GH) deficiency, psychomotor delay with common language disorders, and a distinct phenotype. Evaluation of the hypothalamic-pituitary region by magnetic resonance imaging (MRI) revealed interruption of the pituitary stalk and ectopic posterior pituitary lobe, indicating pituitary malformation associated with permanent GH deficiency prognostic markers. Chromosome analysis prenatally revealed a normal male karyotype with subsequent suspicion of 2q abnormalities on postnatal high-resolution banding. Subsequent array comparative genomic hybridization (array-CGH) identified a de novo complex genome rearrangement consisting of 2p25 duplication and 2q37 deletion: arr[hg19] 2p25.3p25.1(30,341-9,588,369)x3,2q37.2q37.3( 235,744,424-243,041,305)x1. FISH analysis indicated that the abnormal chromosome 2 mimics a derivative of inversion with duplicated 2p regions distal to 2q. To our knowledge, this is the first case of 2p25 duplication and 2q37 deletion with pituitary malformation causing GH deficiency.

A terminal and interstitial deletion at 2p25.3 (<1 Mb in size) detected by array CGH analysis has been reported in approximately 18 patients with shared clinical features including early-onset obesity/overweight associated with intellectual disability (ID) and behavioral issues. This observation suggested an association of 2p subtelomeric deletions with syndromic obesity and led to the hypothesis that MYT1L became a major candidate gene for ID and obesity due to its loss or disruption in all previously reported cases.

Here, we describe a 4.4-year-old girl with moderate ID, early-onset obesity, and attention deficit hyperactivity disorder, who carries a de novo 1.9 Mb terminal deletion of 2p25.3 of paternal origin, detected by array CGH analysis. This deletion disrupts MYT1L and includes five other OMIM genes, ACP1, TMEM18, SNTG2, TPO, and PXDN.

We discuss the potential compound functional effects of additional haploinsufficient genes matching MYT1L heterozygous deletion in syndrome obesity associated with 2p25.5 subtelomeric deletion.

Chromosome 2q37 locus is one of the most commonly deleted subtelomeric regions. Such deletions have been confirmed in over 100 patients by telomere fluorescence in situ hybridization (FISH) analysis and, although less frequently, by array-based comparative genomic hybridization (array CGH). Recognizable “2q37 deletion syndrome” or Albright hereditary osteodystrophy-like syndrome has been previously reported. To better map deletions and refine this deletion syndrome, we collected 14 new patients with intellectual disability characterized by distal or interstitial 2q37 deletions, characterized by FISH and array CGH in collaboration with the French Cytogenetics Association. Patients exhibited facial dysmorphia (13/14), brachydactyly (10/14), associated with behavioral issues, autism or various degrees of autism spectrum disorders, and overweight or obesity. The deletions in these 14 new patients ranged from 2.6 to 8.8 Mb. While the major role of HDAC4 has been established, involvement of several other genes in the deletion region in phenotype remains unclear. We further refine genotype-phenotype correlations of 2q37 deletions. To do this, we examined clinical data, literature review, and Manteia database to investigate minimal overlapping deletion regions for candidate genes for skeletal dysplasia (facial dysmorphia and brachydactyly), overweight, behavioral issues, and seizures. Among the identified candidate genes, we focus on the roles of PRLH, PER2, TWIST2, CAPN10, KIF1A, FARP2, D2HGDH, and PDCD1.

We studied a family where the same 10 Mb inverted duplication of 2p25.3-p25.1 segregates in two children and their father, all of whom exhibit trisomy phenotypes. As the duplication was demonstrated to be inverted by FISH analysis, it was speculated that contiguous terminal deletions may also be present following the classical inv dup del rearrangement. FISH using 2p and 2q subtelomere probes yielded normal results, but array CGH (aCGH) at 100 kb resolution showed a 273 kb deletion in addition to the duplication. Although only one informative spot with normal log ratio was detected, high-resolution aCGH analysis (~20 kb) further suggested the presence of a single-copy region between the deletion and duplication regions. The precise structure of the rearrangement was redefined by real-time PCR and breakpoint cloning, demonstrating the presence of a 2680 bp single-copy sequence between the deletion and duplication regions and implicating simple repeats that could form non-B DNA structures. This rearrangement may not have been mediated by segmental duplications or short inverted repeats, and double-strand breaks may have been repaired by nonhomologous end joining or microhomology-mediated end-joining repair. These data emphasize that accompanying deletions associated with inversions may occur much more frequently than can be demonstrated by classical cytogenetic methods alone. We discuss the impact on trisomy and 2p terminal deletion phenotypes.

We report on a novel patient with terminal deletion of chromosome 2 with breakpoint at 2q36, and five additional novel patients with terminal deletions of 2q with breakpoint at 2q37. A unilateral diaphragmatic hernia is a novel finding in one patient with breakpoint at 2q37.1. Comparing these patients with 60 previously reported individuals with 2q terminal deletions revealed that specific physical abnormalities are broadly associated with breakpoint locations. For instance, patients with breakpoints at or proximal to 2q37.3 frequently exhibited facial features (e.g., prominent forehead, depressed nasal bridge, dysmorphic ears and nose), short stature, and short hands and feet. Reports of horseshoe kidney and Wilms tumor were limited to patients with breakpoint at 2q37.1, while structural brain anomalies and tracheal abnormalities were only reported in patients with breakpoints at or near 2q37.1. Cleft palate was reported only in patients with the most proximal breakpoints (2q36 or 2q35). In this patient cohort, neurological impacts such as developmental delay, intellectual disability, autism-like behaviors, and hypotonia were typical, but severity stratification by breakpoint was not observed. Consideration of terminal deletion of the long arm of chromosome 2 in infants with prominent hypotonia, failure to thrive, gastroesophageal reflux, and developmental delay, and in older children with developmental delay, autism-like behaviors, and characteristic facial and cutaneous features, is warranted. Assigning clinical features to specific breakpoints and refining predictive values may be useful in counseling.

We report on a 13-year-old girl with a potential de novo terminal deletion of chromosome 2q detected by subtelomere FISH analysis despite having a normal karyotype. Further investigation using array CGH analysis with 1 Mb resolution Spectral Chip 2600 (Spectral Genomics) confirmed the deletion and revealed four additional clones with deletions. No other abnormalities were detected by array CGH. FISH studies using eight BAC probes for detailed mapping of the deletion confirmed the array results. FISH analysis revealed that the deletion breakpoint is between clones RP11-84G18 and RP11-83N2 (physical distance between clones is 0.36 Mb) and extends to the telomere. The size of the deletion was estimated to be approximately 6.4–6.7 Mb. Clinical findings included developmental delay, severe behavioral disorders, growth and puberty delay, congenital mild conductive hearing loss, growth hormone deficiency, compensated hypothyroidism, dysmorphic facial features, excessive joint mobility, short middle phalanges, abnormal skin marks, and a history of neonatal laryngomalacia, hypotonia, and umbilical hernia. The phenotype of our patient is consistent with the literature phenotype except for cardiovascular, genitourinary, and neurological abnormalities and eczema not observed. Reporting clinical and molecular symptoms of similar cases may allow for an accurate correlation between phenotype and genotype and appropriate genetic counseling for the family.

We present the rapid diagnosis of aneuploidy involving ring chromosome 2 with microdeletions of 2p25.3 and 2q37.3 using aCGH in uncultured amniocytes from a fetus with intrauterine growth restriction, microcephaly, holoprosencephaly, and ambiguous external genitalia. In our case, holoprosencephaly was added to the list of CNS abnormalities of ring chromosome 2 with microdeletions of 2p25.3 and 2q37.3. We discuss the impact of haploinsufficiency of HDAC4, KIF1A, PASK, HDLBP, FRAP2, and D2HGDH at 2q37.3 and MYT1L, SNTG2, and TPO at 2p25.3 on this case.

Background
The 2q37 deletion syndrome is a rare autosomal dominant disorder caused by deletion of the 2q37 cytoband, resulting in developmental delay, intellectual disability, behavioral abnormalities, and craniofacial dysmorphisms, with over 115 patients reported worldwide.
Case presentation
We report a 3-year-old patient from Colombia with delayed language communication, umbilical hernia, facial dysmorphism, hypotonia, and macrocephaly, imaged with normal magnetic resonance imaging. Microarray-based comparative genomic hybridization revealed a 5.9 Mb deletion in the 2q37.2 and 2q37.3 regions, removing 60 protein-coding genes on one of the chromosomes 2, enabling diagnosis of this patient with 2q37 deletion syndrome. Past interventions included surgical correction of the umbilical hernia.
Conclusion
Genetic testing is a crucial tool not only for diagnosing clinically complex and rare symptoms but also for enabling timely diagnosis for appropriate monitoring, intervention, and genetic counseling. This case extends information on the phenotype and genetic characterization of 2q37 deletion syndrome.

Recently, several reports on interstitial deletions of the short arm terminus of chromosome 3 have been made, aiding in the identification of critical regions responsible for 3p deletion syndrome. We report a case of an 11-year-old girl with intellectual disability, compulsive tendencies, hypotonia, and dysmorphic facies characterized by a 684 kb interstitial 3p25.3 deletion identified by array CGH. This deletion overlaps with three recently reported interstitial 3p25 deletions. These deletions shared a 124 kb overlapping region containing only three RefSeq annotated genes, THUMPD3, SETD5, and LOC440944. This case exhibited phenotypes such as intellectual disability, hypotonia, depressed nasal bridge, long philtrum, similar to those reported previously, but did not exhibit cardiac defects, seizures, or microcephaly reported in cases with larger deletions. Thus, this patient further enhances our understanding of the outcomes of 3p deletions, suggesting correlation between genotype and phenotype.

Terminal 3p deletion syndrome is characterized by developmental delay, low birth weight, growth retardation, microcephaly, brachycephaly, blepharoptosis, long philtrum, micrognathia, low-set ears. We mapped three 3p deletions at the molecular level using FISH and BACs. Deletion sizes ranged from 10.2 to 11 Mb, containing 47-51 known genes including the VHL gene. One deletion was terminal, with an intact 3p telomere. We compared and discussed genotype and phenotype in nine previously reported patients with 3p deletions estimated by molecular or molecular cytogenetic techniques, highlighting candidate genes in these cases. Localizing the proximal breakpoint in one of our patients suggests the narrowed critical region for previously identified cardiac defects, now containing three candidate genes. Deletion of the ATP2B2 gene alone may be insufficient to cause the hearing loss often seen in patients with 3p deletions. This is the third reported case of a terminal 3p interstitial deletion.

Rare 3p deletion syndrome demonstrates a spectrum of abnormalities caused by deletions of various lengths of the short arm of chromosome 3. While many of these deletions involve the terminal 3p, interstitial deletions may also result in the syndrome’s characteristic features. We detected a 643 kb interstitial deletion in a patient displaying many typical features of 3p deletion syndrome. This patient shared several findings with a previously reported patient with a 1.6 Mb interstitial deletion, including cognitive impairment, seizures, and congenital heart defects. The 518 kb overlapping region containing 12 genes was proven crucial for some of these features. We discussed the potential involvement of several genes, such as CRELD1, SRGAP3, CAMK1, TADA3, MTMR14, in the phenotype of 3p deletion syndrome. Our findings suggest that this 518 kb overlapping region may define a critical region for the phenotype of 3p deletion syndrome when deleted.

3p deletion syndrome is a rare disorder caused by deletions of varying sizes in the 3p25-pter region. It is characterized by growth delay, developmental delay, intellectual disability, dysmorphism, microcephaly, and ptosis. The phenotype of individuals with deletions varies from mild to severe. While most cases occur de novo, a few familial cases have been reported. We describe two families with terminal 3p deletions and highly variable clinical features. In family A, both mother and daughter were mildly affected, while the son was more severely affected. In family B, the mother was unaffected, but the son was affected and exhibited symptoms not reported in previous 3p deletion syndrome cases. Deletions were characterized by genome-wide SNP array analysis, with sizes of 9 Mb and 1.1 Mb. Sequence analysis of CHL1, CNTN4, and CRBN genes did not identify any masked recessive alleles potentially explaining the more severe phenotype in the proband of family A. The 9 Mb deletion in family A is presumed to cause the 3p deletion syndrome phenotype in the proband, but the extremely mild phenotype in other family members remains unexplained. In family B, the 1.1 Mb terminal deletion contains only the CHL1 gene, which is insufficient to cause 3p deletion symptoms. This inability to predict the phenotype of offspring based on chromosomal and/or genome-wide array analysis underscores the complexity of 3p deletion syndrome.

We describe two patients with monosomy of the distal portion of the short arm of chromosome 3. One had 46,XX,del(3)(p25.3) and the other 46,XX,r(3)(p26.1q29). The former exhibited clinical symptoms characteristic of 3p- syndrome, including growth retardation, intellectual disability, microcephaly with flat occiput, triangular face, epicanthus, blepharoptosis, telecanthus, broad and flat nasal bridge, long philtrum, downturned mouth, micrognathia, markedly low and malformed ears, digital anomalies, and deafness. The latter had a nonspecific phenotype, including intellectual disability, growth failure, and microcephaly. Comparison of karyotype-phenotype in our case and 16 cases with deletion of the distal portion of 3p from the literature suggests that loss of the 3p25.3 band is crucial for the main clinical manifestations of del(3p) syndrome.

We describe a 1-year-5-month-old female patient referred for genetic evaluation due to neurodevelopmental delay, hearing impairment, and dysmorphism. The patient harbored partial monosomy of chromosome 21(q11.2→q21.3) and terminal monosomy of the 3p chromosome (p25.3→pter) resulting from an unbalanced de novo translocation. The translocation was confirmed by fluorescent in situ hybridization (FISH), with breakpoints mapped by high-resolution array. The final karyotype was defined as 45,XX,der(3)t(3;21)(p25.3;q21.3)dn,-21.ish der(3)t(3;21)(RP11-329A2-,RP11-439F4-,RP11-95E11-,CTB-63H24 +). Analysis of microsatellite DNA markers suggested a paternal origin for the chromosomal rearrangement. This represents the first case of a partial monosomy 21 combined with terminal 3p monosomy due to a de novo unbalanced translocation.

A deletion affecting the terminal of chromosome 3p leads to a characteristic set of clinical symptoms known as 3p- syndrome. Bilateral sensorineural hearing loss (SNHL) is observed in some cases, suggesting a deletion of critical genes in the 3p25 band. To date, no locus causing human hearing loss has been identified in this region. However, the ATP2B2 gene is located at 3p25.3, and haploinsufficiency of its mouse homolog results in similar SNHL severity. We compared the auditory examination results and fine deletion mapping of seven previously unreported 3p- syndrome patients, identifying a 1.38 Mb region at 3p25.3 associated with moderate to severe bilateral SNHL. This new hearing loss locus includes 18 genes, including ATP2B2, which encodes the plasma membrane calcium pump PMCA2. Immunohistochemical analysis of human cochlear sections showed PMCA2 localization in hair cell stereocilia, suggesting its function is conserved between humans and mice. While other genes in this region remain candidates, we conclude that ATP2B2 haploinsufficiency is the most likely cause of SNHL in 3p- syndrome.

Interstitial deletions of the proximal short arm of chromosome 3 (3p) are rare, and a defined clinical phenotype has not been established. We report a 30-month-old girl with an interstitial deletion of chromosome 3p12 (del(3)(p12p12)), distinct facial features (square face, brachycephaly, broad forehead, wide nasal bridge, long philtrum, low-set ears), and psychomotor/language delays. To further characterize proximal 3p deletion syndrome, we compared her clinical features with those of eight previously reported patients with the same deletion.

Ring chromosome 3 (r(3)) is an extremely rare cytogenetic abnormality with clinically heterogeneous presentations, with only 12 cases reported in the literature. We report a 1-year-old girl with r(3), characterized by distinct facial features, developmental delay, and congenital heart defects. G-banding karyotyping and CytoScan 750K-Array revealed a ~10 Mb deletion from chromosome 3pter-p25.3 (61,891-9,979,408), including 42 known genes. Breakpoints were mapped to 3p25.3 and 3q29. We analyzed clinical features of reported r(3) and 3p deletion syndrome cases to provide valuable insights into genotype-phenotype correlations. This is the largest deletion reported in an r(3) case and the second study using whole-genome microarray.

3p deletion syndrome is characterized by distinct facial features, growth retardation, and mental retardation. Typically, individuals with 3p deletion syndrome have terminal deletions from 3p25 to 3pter. We present a child with clinical features consistent with 3p deletion syndrome (ptosis, microcephaly, growth retardation, developmental delay) and a subtle interstitial deletion in the distal short arm of chromosome 3. Fluorescence in situ hybridization (FISH) using 3p subtelomeric probes confirmed the presence of the terminal region of chromosome 3. FISH with BAC clones mapped to chromosome region 3p25-p26 delineated the interstitial deletion to a ~4.5 Mb region between STS markers D3S3630 and D3S1304. This interstitial deletion overlaps with all previously reported terminal deletions in 3p deletion syndrome and represents the smallest reported deletion associated with the syndrome. Characterizing this deletion helps identify genes critical for growth and development when present in hemizygosity.

Background
Deletions of the Wolf-Hirschhorn syndrome critical region (WHSCR-2) on chromosome 4p16.3 typically cause distinct facial features, intellectual disabilities, and prenatal growth retardation. Gains of the same region lead to varying degrees of intellectual disability and dysmorphisms. Similarly, terminal deletions of chromosome 3p (3p deletion syndrome) present with a range of features from mild to severe intellectual disabilities, microcephaly, trigonocephaly, and distinct facial features.
Methods and Results
Chromosomal microarray analysis and fluorescence in situ hybridization revealed complex rearrangements involving chromosome subregions 4p16.1 and 3p26.3, with three individuals showing 4p16.1 deletions and 3p26.3 duplications, and seven individuals showing 4p16.1 duplications and 3p26.3 duplications. All individuals with 4p16.1 deletions and 3p26.3 duplications displayed typical clinical features of WHS. Individuals with 4p16.1 duplications and 3p26.3 duplications exhibited a wide range of clinical features, from typical 3p microdeletion and 4p partial trisomy syndromes to severe neurodevelopmental delay with distinct dysmorphisms.
Conclusion
We present the largest pedigree with complex t(4p;3p) chromosomal rearrangements, showing diverse clinical outcomes, including Wolf-Hirschhorn syndrome, 3p deletion syndrome, and 4p duplication syndrome.

Monosomy 8p is a rare chromosomal abnormality characterized by partial deletion of chromosome 8. The incidence of 8p23.1 deletion is estimated to be 1 in 18,542 amniocentesis samples and 1 in 5,072 postnatal samples.

8p23.1 duplication syndrome (8p23.1 DS) has a high incidence, with an estimated prevalence of 1 in 58,000 individuals.

Distal deletions of 9p are associated with trigonocephaly, intellectual disability, dysmorphic facial features, cardiac anomalies, and genital abnormalities. Previous studies suggest a critical region on band 9p23 between 11.8 Mb and 16 Mb from the 9p telomere. Nine patients displayed clinical features consistent with 9p- syndrome but had smaller terminal deletions than most reported cases. One patient lacked the 9p- phenotype, exhibiting a 140 kb interstitial telomeric deletion inherited from the mother.
Using fluorescence in situ hybridization (FISH) and microarray analysis, we determined the size of each deletion.
Results
The size of deletions ranged from 800 kb to 12.4 Mb in patients with clinically relevant phenotypes. Clinical evaluation and comparison showed minimal differences in physical features based on deletion size. Severe language impairment was observed in all patients with clinically relevant phenotypes.
Conclusion
The smallest common deleted region in our patients with a 9p- phenotype is less than 2 Mb of 9pter, containing six known genes. These genes may contribute to some major features of the 9p deletion syndrome.

We report on two similarly affected cousins, children of monozygotic twin sisters. The cousins exhibit features consistent with 9p deletion syndrome, including trigonocephaly, midface hypoplasia, upward slanting palpebral fissures, long philtrum, intellectual disability, and sexual development anomalies. Initial cytogenetic tests showed normal karyotypes for the proband and her parents. Multiplex ligation-dependent probe amplification revealed a terminal duplication of 1q and a terminal deletion of 9p. Further analysis using FISH identified a familial balanced cryptic translocation t(1;9)(q44;p23) in the mother, highlighting the importance of molecular cytogenetic techniques in clinical genetics.

Purpose
Distal deletions of 9p are associated with trigonocephaly, intellectual disability, dysmorphic facial features, cardiac anomalies, and genital abnormalities. Previous studies suggest a critical region on band 9p23 between 11.8 Mb and 16 Mb from the 9p telomere. Nine patients displayed clinical features consistent with 9p- syndrome but had smaller terminal deletions than most reported cases. One patient lacked the 9p- phenotype, exhibiting a 140 kb interstitial telomeric deletion inherited from the mother.
Methods
Using FISH and microarray analysis, we determined the size of each deletion.
Results
The size of deletions ranged from 800 kb to 12.4 Mb in patients with clinically relevant phenotypes. Clinical evaluation and comparison showed minimal differences in physical features based on deletion size. Severe language impairment was observed in all patients with clinically relevant phenotypes.
Conclusion
The smallest common deleted region in our patients with a 9p- phenotype is less than 2 Mb of 9pter, containing six known genes. These genes may contribute to some major features of the 9p deletion syndrome.

We describe a patient with trigonocephaly and sex reversal, typical of 9p monosomy syndrome. Array comparative genomic hybridization (CGH) revealed a terminal 9 Mb deletion at 9p23. We compared reported cases of 9p monosomy syndrome with trigonocephaly and the associated deletion segments of 9p. Pure terminal or interstitial deletions were compared, identifying a common deleted region of approximately 1 Mb from D9S912 to RP11-439I6 in all patients. We propose that this 1 Mb region is critical for the 9p monosomy syndrome with trigonocephaly.

9p deletion syndrome is caused by partial constitutional monosomy of the short arm of chromosome 9. Clinically, it is characterized by dysmorphic facial features (trigonocephaly, midface hypoplasia, long philtrum), hypotonia, and intellectual disability. The deletions vary in size, and the critical region for the consensus phenotype is reported to be located within a 4-6 Mb interval on 9p22. We analyzed 13 Dutch patients using FISH and, in some cases, array comparative genomic hybridization (array CGH) to determine the deletion breakpoints. No clear genotype-phenotype correlation was established. However, we narrowed the critical region for the 9p deletion syndrome to approximately 300 kb. The CER1 gene, a functional candidate for trigonocephaly, appears to be located just outside this region. Sequencing of CER1 in nine isolated trigonocephaly patients revealed no causative mutations.

9p deletion syndrome is well-characterized and associated with various clinical features such as psychomotor delay, dysmorphisms, and genital anomalies. In contrast, 20p duplication is rarely reported with only a few case studies. The co-occurrence of 9p deletion and 20p duplication has been reported in only four cases. This study aims to investigate the rare chromosomal rearrangement of partial monosomy 9p and partial trisomy 20p in two patients with mirror hand movement. The mirror hand movement was influenced by a combination of genetic and environmental factors. Cases linked to mutations in DCC, NTN1, RAD51, and DNAL4 have been reported, but many cases remain unexplained. Our patients showed no changes in these known genes. This new finding suggests that the genetic basis for mirror hand movement may involve dosage effects of genes within the 9p deletion or 20p duplication regions, or disruption of genes at the breakpoint regions. Further studies focusing on these loci could uncover new etiologies for mirror hand movement.

Chromosome 9p deletion syndrome is a rare autosomal dominant disorder with a wide range of clinical features, including congenital heart defects (CHD). To date, there has been a lack of studies focusing on the cardiac phenotype and function associated with this syndrome. We conducted a multicenter prospective observational study of ten patients diagnosed with 9p deletion syndrome using molecular techniques, providing a complete cardiac evaluation using conventional echocardiography and tissue Doppler imaging echocardiography. The results showed that patients with 9p deletion syndrome, even without major CHD, might exhibit subclinical structural heart changes and left ventricular systolic and diastolic dysfunction. While larger cohorts are needed for confirmation, our findings support the need for comprehensive cardiac evaluation and long-term follow-up in patients with 9p deletion syndrome.

We describe a 5-year-old girl with autism and intellectual disability. Conventional karyotype analysis revealed a novel unbalanced translocation t(11;9)(p15;p23). HumanCytoSNP-12 array analysis identified a 13 Mb deletion from 9p24.3 to 9p23 and a 12.5 Mb duplication from 9p23 to 9p21.2. The karyotype was described as 45,XX,psu dic(11; 9)(p15;p23), reported for the first time. The deletion overlaps with the critical region for monosomy 9p syndrome, containing potential candidate loci for autism spectrum disorder (ASD). The duplication overlaps with the key region for 9p duplication syndrome. These results suggest that seemingly balanced de novo translocations may result in hidden deletions and duplications, and precise mapping of abnormal regions could improve clinical management.

Deletion of the short arm of chromosome 18 is a rare disorder characterized by intellectual disability, growth delay, and craniofacial abnormalities (prominent ears, microcephaly, ptosis, round face). The phenotype spectrum is broad, ranging from mild congenital malformations to holoprosencephaly. We present the case of a 2-year-old girl with ptosis, round face, broad neck with a low hairline, short stature, and pan-hypopituitarism. She underwent artificial ventilation tube placement due to recurrent otitis media. Brain MRI showed ectopic posterior pituitary and poorly visualized pituitary stalk with a shallow and small sella turcica. Cytogenetic and chromosomal microarray analysis revealed a de novo deletion on the short arm of chromosome 18 (arr 18p11.32p11.21[136,227-15,099,116]x1). Diagnosed with growth hormone (GH) deficiency, she has been on recombinant human GH therapy since 6 months of age. Her growth rate improved without side effects from GH therapy. This case expands the phenotypic spectrum of 18p deletion syndrome and underscores the positive impact of GH therapy on linear growth in this syndrome. Further research is needed to elucidate genotype-phenotype correlations and predict prognosis based on deletion size and loci.

18p- syndrome has been known for over 40 years, first reported by de Grouchy et al. [Comptes Rendus Hebdomadaires Séances l’Acad Sci 256 (1963) 1028]. Intellectual disability of varying severity is the most consistent feature. Over 100 cases have been reported, with the oldest patient being 50 years old [Hum Genet 63 (1983) 139; Clin Genet 2 (1971) 338]. Follow-up reports exist for two adult patients, now aged 42 and 62, who were 22 and 42 years old at the time of initial reports [Ann Génét 29 (1986) 107]. More case reports are needed to clarify the long-term course of adults with 18p- syndrome.

We report a 13-year-old girl with 18p deletion syndrome presenting with clinical features similar to Turner syndrome.
Case Report
A 13-year-old girl was referred for genetic counseling due to short stature, short webbed neck, low posterior hairline, puffy eyelids, and increased carrying angle of the elbows, resembling Turner syndrome. She also had mild intellectual disability, psychomotor delay, speech impairment, high arched palate, polydactyly, and midface hypoplasia. Cytogenetic analysis revealed a karyotype of 46,XX,del(18)(p11.2). Her parents had normal karyotypes. Array comparative genomic hybridization (array-CGH) of DNA extracted from peripheral blood identified a 13.93 Mb deletion at 18p11.32-p11.21 (arr 18p11.32p11.21[148,993-14,081,858]x1.0[GRCh37(hg19)]), encompassing 52 Online Mendelian Inheritance in Man (OMIM) genes, including USP14, TYMS, SMCHD1, TGIF1, LAMA1, TWSG1, GNAL, and PTPN2. Polymorphic DNA marker analysis indicated a maternal origin of the deletion.
Conclusion
Females with intellectual disability, dysmorphic features, and psychomotor delay presenting with Turner syndrome-like clinical features should be suspected of having a chromosomal deletion syndrome.

The incidence of 18p deletion syndrome is estimated to be about 1 in 50,000, commonly presenting with short stature, intellectual disability, and dysmorphic facial features. Physical examination of this case showed short stature, intellectual disability, and facial dysmorphisms (microcephaly, ptosis, low nasal bridge, prominent ears, long fingers, thin lips), and clinodactyly of the fifth finger. Karyotype was 46,XX,del(18)(p11.32p11.2). DNA microarray analysis revealed a de novo 13.9 Mb deletion in 18p11.32p11.21. Echocardiography detected asymmetric septal hypertrophy, a rare congenital heart anomaly in this syndrome. This finding suggests that genes involved in heart development may be located in this chromosomal region. Although rare, hypertrophic heart conditions should be considered when evaluating patients with phenotypic abnormalities consistent with 18p deletion syndrome.

Background
The association of behavioral phenotype evaluation with cytogenetic characteristics in syndromes caused by chromosomal abnormalities such as 18p deletion syndrome can enhance our understanding of genotype-phenotype correlations.
Methods
We report on four Brazilian patients with 18p deletion syndrome characterized by cytogenetic methods and detailed neuropsychological evaluation. Intellectual, adaptive, and behavioral characteristics were assessed using Wechsler’s Scale, Vineland-II Scale, and the Child Behavior Checklist, respectively. Socioeconomic indicators, including the education level of the primary caregiver and household income as defined by Brazilian social class classification criteria, were also collected to evaluate the potential contribution of environmental factors to neurocognitive variation.
Results
Two of the four patients exhibited intellectual disability (IQ<70). Results from the Wechsler scale suggested that social situation interpretation based on nonverbal behavior observation constitutes a cognitive strength in our sample, while judgment of social rules and verbal skills related to word knowledge and fluent language abilities might be cognitive weaknesses. Regarding adaptive behavior, Vineland-II Scale indicated that motor skills and socialization were better developed than communication and daily living skills. Only one patient presented internalizing behavior problems based on the Child Behavior Checklist. These results suggest that socioeconomic status might contribute to overall development in these patients.
Conclusion
Our results indicate that some patients with 18p deletion syndrome demonstrate average intelligence, and the size of the deletion and family socioeconomic status may influence cognitive development.

Reason: Chromosome 18p deletion syndrome results from the deletion of all or part of the short arm of chromosome 18. The phenotype of 18p deletion syndrome varies greatly among individuals due to differences in deletion size, breakpoints, and the involved genes. The diverse and atypical clinical presentations make prenatal diagnosis of this syndrome challenging.
Patient Issues: We report four Chinese cases with different chromosome breakpoints. In case 1, a woman with a mild phenotype gave birth to a fetus with severe malformations. The other three cases were diagnosed prenatally. Their phenotypes included increased nuchal translucency (INT) and severe hydronephrosis, indicating a deletion on chromosome 18p. Diagnosis: All four cases were diagnosed with 18p deletion syndrome through karyotype analysis and array-based comparative genomic hybridization (array-CGH).
Intervention: Abnormal chromosomes were analyzed using karyotype analysis and array-based comparative genomic hybridization.
Results: Case 1 and Case 2 showed deletions of 11.51 Mb and 12.39 Mb at 18p11.32p11.21. Case 3 had a 7.1 Mb deletion at 18p11.32p11.23. Case 4 had a 9.9 Mb deletion at 18p11.32p11.22. This report documents for the first time that the same chromosomal breakpoints in mother and offspring can result in significantly different phenotypes. Additionally, we discovered new phenotypes of chromosome 18p deletion syndrome in fetuses, enriching the phenotype spectrum for prenatal diagnosis. Lastly, individuals with identical chromosomal breakpoints may present with varying phenotypes, while individuals with the same breakpoints can exhibit markedly different phenotypes.

We present a patient with a de novo chromosome 18 anomaly involving terminal deletion of 18p and terminal duplication of 18q, along with a subtle interstitial duplication of 18p. This girl had mild dysmorphic features such as micrognathia, cleft palate, bifid uvula, high arched palate, low-set ears, short neck, and full cheeks. She also had an H-type tracheoesophageal fistula requiring surgery. Cognitive and motor skills were delayed. Karyotype analysis revealed additional segments on the short arm of chromosome 18. Chromosomal microarray analysis showed a 7.3 Mb terminal deletion at 18p11.32 to 18p11.23, a 22.2 Mb terminal duplication at 18q21.31 to 18q23, and a 3.9 Mb interstitial duplication at 18p11.22 to 18p11.21. We hypothesize that the mother either has a gonadal mosaicism for normal chromosome 18, der(18)dup(p11.22p11.21), der(18)dup(p11.22p11.21)inv(18)(p11.22q21.31), or both a terminal del/dup and an interstitial duplication arose simultaneously.

The parents’ pericentric inversion of chromosome 18 resulted in a phenotypically normal child with segmental uniparental disomy of 18. We report a familial inversion of chromosome 18, inv(18)(p11.31q21.33). The first child inherited a recombinant chromosome with dup(18q)/del(18p) and a balanced inverted chromosome 18, showing mild dysmorphic features without developmental delay. The second child inherited two recombinant 18 chromosomes, one with dup(18p)/del(18q) from the mother and one with dup(18q)/del(18p) from the father. This chromosome anomaly was detected prenatally, but the family chose to continue the pregnancy, knowing that the two anomalies would complement each other except for the inverted region. Uniparental disomy was confirmed by SNP array. The child, followed up to 20 months of age, is healthy and normal. This case appears to be the first reported instance where two opposing recombinant chromosomes complement each other, resulting in segmental uniparental disomy for two chromosome segments (one maternal and one paternal).

Most chromosomal rearrangements occur through non-allelic homologous recombination mediated by low-copy repeats (LCRs) or segmental duplications (SDs). Recent studies on recombinant chromosome 18 (rec(18)) have focused on diagnosis and clinical phenotype. We diagnosed two prenatal rec(18) cases and identified the exact breakpoint intervals using karyotype and chromosomal microarray analysis. Analyzing the distribution characteristics of repetitive elements at breakpoints, we inferred the mechanisms of rearrangement and reviewed related literature to clarify genetic tendencies. Of 25 pregnancies in 12 families analyzed, 68% had rec(18), 24% had spontaneous abortions, and 8% had normal births. Among 17 rec(18) cases, 65% were maternal in origin, and 35% were paternal. The short arm breakpoint at p11.31 was reported in 10 cases, while long arm breakpoints were at q21.3 (6 cases) and q12 (4 cases). Proximal inversion breakpoints on chromosome 18 are concentrated in regions p11.31, q21.3, and q12. Recurrent rearrangements at 18p11.31 are non-recurrent. ALU, LINE1, and MIR elements are enriched at breakpoint regions (1.85 to 3.42-fold enrichment on chromosome 18), but SDs and LCRs are absent. ALU subfamilies showed 85.94% and 83.01% sequence identity between breakpoint pairs. Small repetitive elements may mediate recombination and DNA repair processes, promoting rearrangement on chromosome 18. Maternal inversion carriers are prone to aberrant recombination in rec(18) pedigrees. Recombinant chromosomes may show preferential segregation during gametogenesis.

Carriers of chromosome 18 translocations may have offspring with recombinant chromosomes, resulting in patients with various clinical symptoms. Patients with 18p-/18q+ rearrangements share several clinical features, but other features vary, possibly due to the length of the inverted segment. Here, we describe a Peruvian child with dysmorphisms, intellectual disability, persistent microscopic hematuria, aortic pseudoaneurysm, and descending aortitis. Family karyotype analysis revealed that the mother is a carrier of a pericentric inversion, inv(18)(p11.2q21.3). The child has a recombinant chromosome 18, and chromosomal microarray analysis detected two genomic imbalances on chromosome 18. Persistent microscopic hematuria has not been reported in 18p-/18q+ phenotypes. This case highlights unknown factors that may play a critical role in these types of recombinant chromosomes, revealing genotype-phenotype correlations or features that manifest as the patient ages.

Recent studies have shown that 4.7% of all reported chromosomal abnormalities involve deletions, including microdeletions, resulting in a prevalence rate of 1.99 per 10,000 births (3). Duplications are even less common, indicating a prevalence rate of 0.7 per 10,000 births, equivalent to 1.6% of all reported chromosomal abnormalities (3).

Autosomal recessive (AR) disorders constitute a significant portion of inherited disorders and are a cause of considerable disease burden. They affect approximately 1.75-5 individuals per 1000 newborns (compared to 1.4 individuals per 1000 newborns in autosomal dominant disorders).