Distal 1p Research Articles

The Phenotypic Spectrum of 16p11.2 Recurrent Chromosomal Rearrangements.

The human 16p11.2 chromosomal region is rich in segmental duplications which mediate the formation of recurrent CNVs. CNVs affecting the 16p11.2 region are associated with an increased risk for developing neuropsychiatric disorders, including autism spectrum disorder (ASD), schizophrenia, and intellectual disability (ID), as well as abnormal body weight and head circumference and dysmorphic features, with marked phenotypic variability and reduced penetrance. CNVs affecting the 16p11.2 region mainly affect a distal interval of ~220 Kb, between Breakpoints 2 and 3 (BP2-BP3), and a proximal interval of ~593 Kb (BP4-BP5). Here, we report on 15 patients with recurrent 16p11.2 rearrangements that were identified among a cohort of 1600 patients (0.9%) with neurodevelopmental disorders. A total of 13 deletions and two duplications were identified, of which eight deletions included the proximal 16p11.2 region (BP4-BP5) and five included the distal 16p11.2 region (BP2-BP3). Of the two duplications that were identified, one affected the proximal and one the distal 16p11.2 region; however, both patients had additional CNVs contributing to phenotypic severity. The features observed and their severity varied greatly, even between patients within the same family. This article aims to further delineate the clinical spectrum of patients with 16p11.2 recurrent rearrangements in order to aid the counselling of patients and their families.

Evaluation of 100 Dutch cases with 16p11.2 deletion and duplication syndromes; from clinical manifestations towards personalized treatment options

The 16p11.2 deletion syndrome is a clinically heterogeneous disorder, characterized by developmental delay, intellectual disability, hyperphagia, obesity, macrocephaly and psychiatric problems. Cases with 16p11.2 duplication syndrome have similar neurodevelopmental problems, but typically show a partial ‘mirror phenotype’ with underweight and microcephaly. Various copy number variants (CNVs) of the chromosomal 16p11.2 region have been described. Most is known about the ‘typical’ 16p11.2 BP4-BP5 (29.6–30.2 Mb; ~600 kb) deletions and duplications, but there are also several published cohorts with more distal 16p11.2 BP2-BP3 CNVs (28.8–29.0 Mb; ~220 kb), who exhibit clinical overlap. We assessed 100 cases with various pathogenic 16p11.2 CNVs and compared their clinical characteristics to provide more clear genotype-phenotype correlations and raise awareness of the different 16p11.2 CNVs. Neurodevelopmental and weight issues were reported in the majority of cases. Cases with distal 16p11.2 BP2-BP3 deletion showed the most severe obesity phenotype (73.7% obesity, mean BMI SDS 3.2). In addition to the more well defined typical 16p11.2 BP4-BP5 and distal 16p11.2 BP2-BP3 CNVs, we describe the clinical features of five cases with other, overlapping, 16p11.2 CNVs in more detail. Interestingly, four cases had a second genetic diagnosis and 18 cases an additional gene variant of uncertain significance, that could potentially help explain the cases’ phenotypes. In conclusion, we provide an overview of our Dutch cohort of cases with various pathogenic 16p11.2 CNVs and relevant second genetic findings, that can aid in adequately recognizing, diagnosing and counseling of individuals with 16p11.2 CNVs, and describe the personalized medicine for cases with these conditions.

The Phenotypic variability of 16p11.2 distal BP2–BP3 deletion in a transgenerational family and in neurodevelopmentally ascertained samples

BackgroundWe present genomic and phenotypic findings of a transgenerational family consisting of three male offspring, each with a maternally inherited distal 220 kb deletion at locus 16p11.2 (BP2–BP3). Genomic analysis...

Chromosome 1p status in neuroblastoma correlates with higher expression levels of miRNAs targeting neuronal differentiation pathway.

Neuroblastoma (NB) is characterized by acquired segmental and numerical chromosome aberrations. Although deletions of distal 1p and 11q are frequent alterations, no candidate tumor suppressor gene residing in these chromosomal sites could be identified so far. In the present study, we detected the genomic imbalances of six neuroblastoma cell lines using the multiplex ligation-dependent probe amplification (MLPA) technique and the microRNA (miRNA) expression profiles of the cell lines by a microarray study. According to MLPA results, we aimed to assess the miRNA expression profiles of the cell lines harboring 11q and 1p deletions. The cell lines with 1p deletions revealed statistically significant higher levels of expression for 29 miRNAs in contrast to the cell lines without 1p deletion in microarray study. We also performed GO enrichment analysis for predicted targets of the differentially expressed miRNAs. According to GO enrichment analysis, miRNAs that showed the high change in expression was associated with neuronal differentiation. We showed that hsa-miR-494, hsa-miR-495, and hsa-miR-543 target most of mRNAs in neuronal differentiation pathway. Although limited to the cell lines, our results highly suggest that NBs with different segmental chromosome abnormalities may have different dysregulated miRNA expression signatures that target the genes involved in neuronal differentiation.

Molecular cytogenetic characterization of de novo concomitant distal 8p deletion of 8p23.3p23.1 and Xp and Xq deletion of Xp22.13q28 due to an unbalanced X;8 translocation detected by amniocentesis

ObjectiveWe present molecular cytogenetic characterization of de novo concomitant distal 8p deletion of 8p23.3p23.1 and Xp and Xq deletion of Xp22.13q28 due to an unbalanced X;8 translocation detected by amniocentesis. Case reportA 33-year-old primigravid woman underwent amniocentesis at 18 weeks of gestation because of a Down syndrome risk of 1/52 at the first-trimester maternal serum screening calculated from 0.29 multiples of the median (MoM) of pregnancy associated plasma protein-A (PAPP-A), 1.14 MoM of free β-hCG and 0.46 MoM of placental growth factor (PlGF). Amniocentesis revealed a karyotype of 45,X,add(8)(p23.1). The parental karyotypes were normal. Array comparative genomic hybridization (aCGH) analysis on the DNA extracted from cultured amniocytes revealed a 137-Mb deletion of Xp22.13q28 and a 10.53-Mb deletion of 8p23.3p23.1. The karyotype thus was 45,X,der(8)t(X;8)(p22.13;p23.1). Prenatal ultrasound revealed pericardial effusion and skin edema. The pregnancy was subsequently terminated, and a 568-g malformed fetus was delivered with hypertelorism and low-set ears. The cord blood had a karyotype of 45,X,der(8)t(X;8)(p22.13;p23.1). aCGH analysis of the cord blood revealed the result of arr [GRCH37 (hg19)] 8p23.3p23.1 (191,530–10,724,642) × 1.0, arr Xp22.13q28 (18,194,098–155,232,907) × 1.0. ConclusionaCGH analysis is useful elucidating the genetic nature of an aberrant chromosome with an additional maternal of unknown origin attached to a chromosome terminal region.

EP101: The diagnostic odyssey towards detection of mosaic distal 5p tetrasomy through buccal swab DNA analysis

Somatic mosaicism for pathogenic genetic variants can explain the clinical findings of individuals with highly suspected genetic disorders who have uninformative results on genetic analysis of peripheral blood mononuclear cells (PBMCs). Indeed, mosaic small supernumerary chromosomes may be undetected in tissues with high cellular turnover, such as PBMCs, due to their intrinsic instability during mitosis. Features suggestive of somatic mosaicism include segmental pigmentary skin or hair changes, body asymmetry, and mild presentations of well-characterized syndromes such as Trisomy 21.

Translational Study of Copy Number Variations in Schizophrenia.

Rare copy number variations (CNVs) are part of the genetics of schizophrenia; they are highly heterogeneous and personalized. The CNV Analysis Group of the Psychiatric Genomic Consortium (PGC) conducted a large-scale analysis and discovered that recurrent CNVs at eight genetic loci were pathogenic to schizophrenia, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.23, 15q13.3, distal 16p11.2, proximal 16p11.2, and 22q11.2. We adopted a two-stage strategy to translate this knowledge into clinical psychiatric practice. As a screening test, we first developed a real-time quantitative PCR (RT-qPCR) panel that simultaneously detected these pathogenic CNVs. Then, we tested the utility of this screening panel by investigating a sample of 557 patients with schizophrenia. Chromosomal microarray analysis (CMA) was used to confirm positive cases from the screening test. We detected and confirmed thirteen patients who carried CNVs at these hot loci, including two patients at 1q21.1, one patient at 7q11.2, three patients at 15q13.3, two patients at 16p11.2, and five patients at 22q11.2. The detection rate in this sample was 2.3%, and the concordance rate between the RT-qPCR test panel and CMA was 100%. Our results suggest that a two-stage approach is cost-effective and reliable in achieving etiological diagnosis for some patients with schizophrenia and improving the understanding of schizophrenia genetics.

49. Cryptic Triple Hit Lymphoma: What's hiding in those chromosomes? A chromosome, FISH and microarray story

High-grade B-cell lymphoma with concurrent MYC, BCL2, and BCL6 rearrangements (i.e. Triple Hit Lymphoma (TH)) is an aggressive lymphoma generally detected by conventional cytogenetics and/or FISH. We present a patient referred for high grade diffuse large B-cell lymphoma with a complex karyotype. The diagnosis was consistent with follicular lymphoma and clonal evolution, based only on the karyotype analysis. Dual fusion and breakapart (BAP) FISH strategies and microarray testing were required to diagnosis TH lymphoma. The karyotype included a t(14;18) with an extra derivative 14 (no normal 14), a t(3;22)(q27;q11.2), a t(2;6) and trisomy 8. IGH/BCL2 FISH identified three fusions, consistent with the novel double derivative (14)t(14;18) and derivative 18. BCL2 -BAP FISH showed one germline fusion, a 3’ signal and two 5’ signals rather than the typical evolution related extra 3’ signal, but consistent with the double derivative 14. MYC-BAP FISH showed three un-rearranged fusions discordant with the double fusion IGH/MYC result. This apparent incongruence could be explained by an IGH insertion into MYC which was confirmed by metaphase FISH. The BCL6 FISH was also atypical with 2 germ line fusions and a small extra 5’ BCL6 signal. Since the microarray showed no 3q27 gain, a balanced rearrangement between the 5’BCL6 promotor and the lambda-light gene at 22q11.2 was concluded. Copy neutral LOH (CN-LOH) of 14q32.13->qter in the array analysis (spanning IGH) supports mitotic recombination based clonal evolution for the novel double derivative 14, consistent with a reversal of the common oncogenic fusion derivative. A second CN-LOH region was observed spanning distal 6p, although the driver gene for that evolution is not clear. In summary, the TH would have been missed without multiple disciplinary ancillary testing, highlighting their importance in accurately evaluating complex clones in facilitating optimal patient care and management.

Neurological disorder-associated genetic variants in individuals with psychogenic nonepileptic seizures

Psychogenic nonepileptic seizures (PNES) are diagnosed in approximately 30% of patients referred to tertiary care epilepsy centers. Little is known about the molecular pathology of PNES, much less about possible underlying genetic factors. We generated whole-exome sequencing and whole-genome genotyping data to identify rare, pathogenic (P) or likely pathogenic (LP) variants in 102 individuals with PNES and 448 individuals with focal (FE) or generalized (GE) epilepsy. Variants were classified for all individuals based on the ACMG-AMP 2015 guidelines. For research purposes only, we considered genes associated with neurological or psychiatric disorders as candidate genes for PNES. We observe in this first genetic investigation of PNES that six (5.88%) individuals with PNES without coexistent epilepsy carry P/LP variants (deletions at 10q11.22-q11.23, 10q23.1-q23.2, distal 16p11.2, and 17p13.3, and nonsynonymous variants in NSD1 and GABRA5). Notably, the burden of P/LP variants among the individuals with PNES was similar and not significantly different to the burden observed in the individuals with FE (3.05%) or GE (1.82%) (PNES vs. FE vs. GE (3 × 2 χ2), P = 0.30; PNES vs. epilepsy (2 × 2 χ2), P = 0.14). The presence of variants in genes associated with monogenic forms of neurological and psychiatric disorders in individuals with PNES shows that genetic factors are likely to play a role in PNES or its comorbidities in a subset of individuals. Future large-scale genetic research studies are needed to further corroborate these interesting findings in PNES.

Clinical and genetic findings in Hungarian pediatric patients carrying chromosome 16p copy number variants and a review of the literature

The short arm of chromosome 16 (16p) is enriched for segmental duplications, making it susceptible to recurrent, reciprocal rearrangements implicated in the etiology of several phenotypes, including intellectual disability, speech disorders, developmental coordination disorder, autism spectrum disorders, attention deficit hyperactivity disorders, obesity and congenital skeletal disorders. In our clinical study 73 patients were analyzed by chromosomal microarray, and results were confirmed by fluorescence in situ hybridization or polymerase chain reaction. All patients underwent detailed clinical evaluation, with special emphasis on behavioral symptoms. 16p rearrangements were identified in 10 individuals. We found six pathogenic deletions and duplications of the recurrent regions within 16p11.2: one patient had a deletion of the distal 16p11.2 region associated with obesity, while four individuals had duplications, and one patient a deletion of the proximal 16p11.2 region. The other four patients carried 16p variations as second-site genomic alterations, acting as possible modifying genetic factors. We present the phenotypic and genotypic results of our patients and discuss our findings in relation to the available literature.

Distal 3p Duplication and 22q13.3 Deletion with Severe Hypotonia Originating from a Paternal Balanced Translocation (3;22)

In this study, we present a case with distal 3p duplication and 22q13.3 deletion due to unbalanced meiotic segregation in her father carrying a balanced translocation. The 2-month-old girl was examined for her severe hypotonia, developmental delay, and mild dysmorphic appearance. Clinical features include broad forehead, hypertelorism, laterally extended eyebrows, long eyelashes, a depressed nasal root, bifid nasal tip, long philtrum, thin lips, posteriorly rotated ears, short neck, partial syndactyly of the right hand (fingers 3, 4) , and partial syndactyly of the right foot (toes 2, 3). After examination, the final karyotype was reported as: 46,XX,der(22)del(22)(qter)dup(3)(p22pter), and the array-CGH results showed arr[GRCh37] 3p26.3p22.1(93949_41518607)×3 and arr[GRCh37] 22q13.31q13.33(44554083_51224252)×1. The mother has a 46,XX karyotype, and her father carries a balanced translocation, 46,XY,t(3;22)(p26.3;q13.3). This is the first case with a distal 3p duplication and 22q13.3 deletion with severe hypotonia and developmental delay.

Wolf–Hirschhorn syndrome: Prenatal diagnosis and molecular cytogenetic characterization of a de novo distal deletion of 4p (4p16.1 → pter) in a fetus with facial cleft and preaxial polydactyly

ObjectiveWe present prenatal diagnosis and molecular cytogenetic characterization of Wolf–Hirschhorn syndrome (WHS) in a fetus with facial cleft and preaxial polydactyly. Materials and methodsA 37-year-old woman underwent amniocentesis at 18 weeks of gestation because of advanced maternal age, and the result showed an aberrant chromosome 4 or 46,XX,add(4) (p15.3). The woman consulted our clinics at 22 weeks of gestation and requested for repeat amniocentesis. Prenatal ultrasound revealed intrauterine growth restriction, facial cleft, vermian hypoplasia of cerebellum, micrognathia and absent stomach. Conventional cytogenetic analysis was performed on cultured amniocytes, parental bloods and cord blood. Array comparative genomic hybridization (aCGH) and quantitative fluorescent polymerase chain reaction (QF-PCR) were performed on the DNAs extracted from uncultured amniocytes and parental bloods. Fluorescence in situ hybridization (FISH) analysis was performed on cultured metaphase amniocytes. ResultsaCGH analysis on uncultured amniocytes revealed arr 4p16.3p16.1 (74,447–8,732,731) × 1.0 [GRCh37 (hg19)] with an 8.66-Mb deletion of 4p16.3-p16.1 encompassing 70 [Online Mendelian Inheritance of in Man (OMIM)] genes including ZNF141, FGFRL1, TACC3, LETM1, NSD2 and NELFA. QF-PCR revealed a paternal origin of the distal 4p deletion. Conventional cytogenetic analysis revealed 46,XX,del(4) (p16.1)dn in the fetus. Metaphase FISH analysis confirmed a 4p16 deletion. The parental karyotypes were normal. The pregnancy was subsequently terminated, and a malformed fetus was delivered with typical WHS facial dysmorphism, bilateral cleft lip and palate, and preaxial polydactyly on the right hand. ConclusionaCGH, QF-PCR and FISH help to delineate the nature of a prenatally defected aberrant chromosome, and the acquired information is useful for genetic counseling.

Large 1p36 Deletions Affecting Arid1a Locus Facilitate Mycn-Driven Oncogenesis in Neuroblastoma

SUMMARYLoss of heterozygosity (LOH) at 1p36 occurs in multiple cancers, including neuroblastoma (NBL). MYCN amplification and 1p36 deletions tightly correlate with markers of tumor aggressiveness in NBL. Although distal 1p36 losses associate with single-copy MYCN tumors, larger deletions correlate with MYCN amplification, indicating two tumor suppressor regions in 1p36, only one of which facilitates MYCN oncogenesis. To better define this region, we genome-edited the syntenic 1p36 locus in primary mouse neural crest cells (NCCs), a putative NBL cell of origin. In in vitro cell transformation assays, we show that Chd5 loss confers most of the MYCN-independent tumor suppressor effects of 1p36 LOH. In contrast, MYCN-driven tumorigenesis selects for NCCs with Arid1a deletions from a pool of NCCs with randomly sized 1p36 deletions, establishing Arid1a as the MYCN-associated tumor suppressor. Our findings reveal that Arid1a loss collaborates with oncogenic MYCN and better define the tumor suppressor functions of 1p36 LOH in NBL.

Partial Monosomy 4p and Trisomy 12q due to a t(4;12)(p16.3;q24.31) Familial Translocation in Two Cousins

Wolf-Hirschhorn syndrome (WHS) is caused by a distal 4p monosomy usually involving the region of the WHSC1 and WHSC2 genes. About 40-45% of WHS patients show an unbalanced translocation leading to both 4p monosomy and partial trisomy of another chromosome arm. In this case report, we describe 2 female cousins (P1 and P2) with a derivative chromosome leading to a 4p16.3pter deletion and 12q24.31qter duplication. Conventional karyotyping and genomic analyses showed that they both had the same rearrangement derived from a balanced parental translocation involving chromosomes 4 and 12, t(4;12)(p16.3;q24.31). The rearrangements occurred between 4p16.3pter and 12q24.31qter detected by array-CGH analysis, with a 2.7-Mb loss at 4p and a large 12.4-Mb gain at 12q. Both affected patients shared global developmental delay and craniofacial dysmorphisms with some distinct phenotypic findings associated with both WHS and 12qter trisomy. P2 was more severely impaired than P1, and she showed severe intellectual disability, seizures, midface hypoplasia, unilateral microtia, and deafness which were absent in P1. Previous studies of distal 4p monosomies have found phenotypic variability in WHS which does not correlate with haploinsufficiency of specific genes. Features of 12q trisomies are diverse with developmental and growth delay, intellectual disability, behavioral problems, and facial abnormalities. Collectively, our analysis of the literature of 3 similar translocations involving 4p and 12q, together with the clinical features of the affected cousins in this familial translocation, permits an evaluation of genes closely linked to WHSC1 and WHSC2 in the context of WHS and the genes involved in 12q trisomy.

Chromosome 3p Inverted Duplication with Terminal Deletion: Second Postnatal Case Report with Additional Clinical Features

Distal deletions and duplications of 3p are individually well-characterized chromosome abnormalities. Here, we report an inverted duplication of 3p with an adjacent terminal 3p deletion in a 17-month-old girl who had prenatal intrauterine growth restriction and cardiac defects. Other findings included hemangiomas, neutropenia, umbilical hernia, hypotonia, gross motor delay, microcephaly, and ptosis. Family history was noncontributory. Microarray analysis revealed a 5.37 Mb deletion of chromosome bands 3p26.1 to 3p26.3 and a 13.68 Mb duplication of 3p24.3 to 3p26.1. FISH analysis confirmed that the duplication was inverted. Upon literature review, only one postnatal patient and one second trimester pregnancy have been reported with this finding. Many of our patient's features are present in both 3p deletion and 3p duplication syndromes, including congenital heart disease, growth restriction, microcephaly, hypotonia, and developmental delay. Our patient has additional features not commonly reported in 3p deletion or duplication patients, such as aortic dilation, hemangiomas, and neutropenia. The identification of this patient contributes to additional understanding of features associated with concurrent deletion and inverted duplication in the distal 3p chromosome. This report may assist clinicians working with patients who have constellations of similar features or similar cytogenomic abnormalities.

Prenatal diagnosis for a pedigree affected with Wolf-Hirschhorn syndrome due to a subtle chromosomal translocation

To make molecular diagnosis of an infant affected with severe developmental delay and multiple birth defects, assisting prenatal diagnosis for the second pregnancy. Standard G-banded karyotyping was performed for the fetus and his parents. Single nucleotide polymorphism array (SNP array) was used to detect submicroscopic chromosomal aberration. Fluorescence in situ hybridization (FISH) was employed to determine the parental origin of the aberration. Both the proband and the fetus harbored a 5.4 Mb distal 4p deletion and a 6.9 Mb distal 6q duplication. FISH confirmed that the mother has carried a balanced translocation involving 4p and 6q. The unbalanced chromosomal aberration in the proband and the fetus were both derived from the mother. Both patients showed a Wolf-Hirschhorn syndrom phenotype and partial phenotype of 6q trisomy. SNP array combined with FISH are essential for the detection of cryptic chromosomal aberrations which may be missed by coventional karyotyping analysis.

Distal chromosome 16p11.2 duplications containing SH2B1 in patients with scoliosis

IntroductionAdolescent idiopathic scoliosis (AIS) is a common musculoskeletal disorder with strong evidence for a genetic contribution. CNVs play an important role in congenital scoliosis, but their role in idiopathic scoliosis...

SA25 - AN INHERITED DISTAL 16P11.2 DELETION DEMONSTRATES VARIABLE EXPRESSIVITY AND INCOMPLETE PENETRANCE FOR PSYCHIATRIC ILLNESS AS WELL AS ASSOCIATION WITH RHIZOMELIC SHORTENING: A CASE REPORT

Background The most commonly reported 16p Copy Number Variant (CNV) - 16p11.2 deletion syndrome (16pDS) (~600 kb; 29.5 -30.1 Mb) – has been robustly associated with schizophrenia (SZ), as well as Intellectual Disabilities (ID)/Developmental Delays (DD), congenital anomalies, dysmorphic features and obesity. Non-overlapping “distal” 16p11.2 deletions (~200 kb; 28.7 -28.9 Mb) are less commonly reported, but have a variable phenotype similar to that of 16pDS, including emerging data suggesting a psychiatric phenotype. We report here on a parent/child dyad who share a distal 16p11.2 deletion. Methods Patient 1 (index) was assessed (for indications including seizures, DD, and short limbs) at ages 2, 17, and 36, when she had clinical Chromosomal Microarray (CMA) (Affymetrix Cytoscan HD array, clinical thresholds: 200 kb (deletions), 400 kb (duplications), Chromosome Analysis suite (v2.0.0 195)). Fluorescence in Situ Hybridization (FISH) was used to confirm the deletion and determine origin. Results Patient 1 was born at term to non-consanguineous parents. A 46XX karyotype was confirmed at age 2 and 17 (testing indications: myoclonic seizures, DD, rhizomelic shortening of upper limbs). At age 17, she was also noted to have small hands ( Discussion While distal 16p11.2 deletions have been shown to increase risk for schizophrenia, this report contributes to the emerging evidence that this CNV is also associated with broader psychiatric phenotypes, such as bipolar disorder. The father's milder cognitive and metabolic phenotype supports variable expressivity of distal 16p11.2 deletions, even when inherited; his negative psychiatric history reinforces the incomplete penetrance of this CNV for psychiatric disorders. This report also contributes to the generation of a more thorough clinical description of the phenotypic range of distal 16p11.2 deletion, which we suggest, includes rhizomelic limb shortening.

Diagnostic distal 16p11.2 deletion in a preterm infant with facial dysmorphism

The 16p11.2 microdeletion has been reported in patients with developmental delays and intellectual disability. The distal 220-kb deletion in 16p11.2...

A boy with developmental delay and mosaic supernumerary inv dup(5)(p15.33p15.1) leading to distal 5p tetrasomy \u2013 case report and review of the literature

BackgroundWith only 11 patients reported, 5p tetrasomy belongs to rare postnatal findings. Most cases are due to small supernumerary marker chromosomes (sSMCs) or isochromosomes. The patients share common but unspecific symptoms such as developmental delay, seizures, ventriculomegaly, hypotonia, and fifth finger clinodactyly. Simple interstitial duplications leading to trisomies of parts of 5p are much more frequent and better described. Duplications encompassing 5p13.2 cause a defined syndrome with macrocephaly, distinct facial phenotype, heart defects, talipes equinovarus, feeding difficulties, respiratory distress and anomalies of the central nervous system, developmental delay and hypotonia.Case presentationWe present a boy with dysmorphic features, developmental delay, intellectual disability and congenital anomalies, and a mosaic sSMC inv dup(5)(p15.33p15.1). He is the fourth and the oldest reported patient with distal 5p tetrasomy. His level of mosaicism was significantly different in lymphocytes (13.2%) and buccal cells (64.7%). The amplification in our patient is smaller than that in the three previously published patients but the only phenotype difference is the absence of seizures in our patient.ConclusionsOur observations indicate that for the assessment of prognosis, especially with respect to intellectual functioning, the level of mosaicism could be more important than the extent of amplification and the number of extra copies. Evaluation of the phenotypical effect of rare chromosomal aberrations is challenging and each additional case is valuable for refinement of the genotype-phenotype correlation. Moreover, our patient demonstrates that if the phenotype is severe and if the level of sSMC mosaicism is low in lymphocytes, other tissues should be tested.