Prenatal diagnosis and molecular cytogenetic characterization of a de novo proximal interstitial deletion of chromosome 4p (4p15.2→p14)

We present prenatal diagnosis of de novo proximal interstitial deletion of chromosome 4p (4p15.2→p14) and molecular cytogenetic characterization of the deletion using uncultured amniocytes. We review the phenotypic abnormalities of previously reported patients with similar proximal interstitial 4p deletions, and we discuss the functions of the genes of RBPJ, CCKAR, STIM2, PCDH7 and ARAP2 that are deleted within this region.     

Disruption of Contactin 4 in two subjects with autism in Chinese population

Autism is a heterogeneous childhood neurodevelopmental disorder that is characterised by deficits in verbal communication, impaired social interactions, restricted interests and repetitive behaviours. Using an Illumina HumanCNV370-Quad BeadChip, we identified two Han Chinese individuals with autism and large duplications (~1.6 Mb and ~2.4 Mb) disrupting the same CNTN4 gene. CNTN4 encodes a protein that functions as a cell-adhesion molecule and may play an essential role in the formation of axon connections in the developing nervous system. The disruption of this gene has been reported to be the cause of the 3p deletion syndrome and also a possible susceptibility factor for autism spectrum disorders (ASDs). Our results suggest that rare copy number variations (CNVs) in CNTN4 may also influence autism susceptibility in Asian populations. Interestingly, a comparison of the clinical phenotypes between the two subjects revealed that the subject with the 2.4 Mb CNV (involving several other genes) presented with a more severe phenotype than the subject with the 1.6 Mb CNV (disrupting only CNTN4 and CNTN6). This suggests that other genes in the nearby region may contribute to the pathogenesis.     

A de novo interstitial deletion of 8p11.2 including ANK1 identified in a patient with spherocytosis, psychomotor developmental delay, and distinctive facial features

The contiguous gene syndrome involving 8p11.2 is recognized as a combined phenotype of both Kallmann syndrome and hereditary spherocytosis, because the genes responsible for these 2 clinical entities, the fibroblast growth factor receptor 1 (FGFR1) and ankyrin 1 (ANK1) genes, respectively, are located in this region within a distance of 3.2Mb. We identified a 3.7Mb deletion of 8p11.2 in a 19-month-old female patient with hereditary spherocytosis. The identified deletion included ANK1, but not FGFR1, which is consistent with the absence of any phenotype or laboratory findings of Kallmann syndrome. Compared with the previous studies, the deletion identified in this study was located on the proximal end of 8p, indicating a pure interstitial deletion of 8p11.21. This patient exhibited mild developmental delay and distinctive facial findings in addition to hereditary spherocytosis. Thus, some of the genes included in the deleted region would be related to these symptoms.     

1.5 Mb deletion of chromosome 4p16.3 associated with postnatal growth delay,psychomotor impairment,epilepsy, impulsive behavior and asynchronous skeletal development

Several Wolf-Hirschhorn syndrome patients have been studied, mouse models for a few candidate genes have been constructed and two WHS critical regions have been postulated, but the molecular basis of the syndrome remains poorly understood.     

Prenatal diagnosis of partial trisomy 3q (3q27.3→qter) and partial monosomy 14q (14q31.3→qter) of paternal origin associated with fetal hypotonia,arthrogryposis, scoliosis and hyperextensible joints

We present rapid aneuploidy diagnosis of partial trisomy 3q (3q27.3→qter) and partial monosomy 14q (14q31.3→qter) of paternal origin by aCGH using uncultured amniocytes in a fetus with hypotonia, scoliosis, arthrogryposis, hyperextensible joints, facial dysmorphism, ventricular septal defect, pulmonary stenosis, clenched hands, clubfoot, scalp edema and right hydronephrosis. We discuss the genotype–phenotype correlation of 3q duplication syndrome and terminal 14q deletion syndrome. We demonstrate that fetuses with a paternal-origin deletion of 14q involving the 14q32.2 imprinted region may prenatally present the upd(14)mat-like phenotype such as hypotonia, scoliosis, arthrogryposis and hyperextensible joints.     

Xp22.3 interstitial deletion: A recognizable chromosomal abnormality encompassing VCX3A and STS genes in a patient with X-linked ichthyosis and mental retardation

X-linked ichthyosis is a genetic disorder affecting the skin and caused by a deficit in the steroid sulfatase enzyme (STS), often associated with a recurrent microdeletion at Xp22.31. Most of the STS deleted patients have X-linked ichthyosis as the only clinical feature and it is believed that patients with more complex disorders including mental retardation could be present as a result of contiguous gene deletion. In fact, VCX3A gene, a member of the VCX (variable charge, X chromosome) gene family, was previously proposed as the candidate gene for X-linked non-specific mental retardation in patients with X-linked ichthyosis.     

Prenatal diagnosis and molecular cytogenetic characterization of de novo partial trisomy 12q (12q24.21 → qter) and partial monosomy 6q (6q27 → qter) associated with coarctation of the aorta,ventriculomegaly and thickened nuchal fold

We present rapid aneuploidy diagnosis of de novo partial trisomy 12q (12q24.21 → qter) and partial monosomy 6q (6q27 → qter) by aCGH using uncultured amniocytes in a fetus with coarctation of the aorta, ventriculomegaly and thickened nuchal fold. We discuss the association of TBX3, TBX5 and MED13L gene duplication with coarctation of the aorta, and the association of RNASET2 gene haploinsufficiency with ventriculomegaly in this case.     

A parallel study of different array-CGH platforms in a set of Spanish patients with developmental delay and intellectual disability

Developmental delay and intellectual disability, which occur in 1–3% of the population, account for a large number of the cases regularly seen in genetic units. Chromosomal microarray analysis has been shown to be a valuable clinical diagnostic assay and it should be the first-tier clinical diagnostic test for individuals with these conditions. However and due to several difficulties such as the platform resolution, the cost, and the inexperience with genomic data bases, the implementation of this test in many cytogenetic laboratories has been delayed. In an attempt to provide more insights of the benefits derived by using the chromosomal microarray analysis, this study presents the experience of two clinical centers using three different microarray platforms. The results obtained using a custom microarray (KaryoArray®) and two different commercial medium- and high-resolution whole-genome oligonucleotide microarrays have been compared. An overall diagnostic yield of around 15% has been obtained. However, the custom microarray platform has been shown to be more convenient for a clinical setting, since it allows the detection of more pathogenic copy number variants and less common variants.     

A 1.5 Mb terminal deletion of 12p associated with autism spectrum disorder

We report a patient with a terminal 12p deletion associated with autism spectrum disorder (ASD). This 12p13.33 deletion is 1.5 Mb in size and encompasses 13 genes (B4GALNT3, CCDC77, ERC1, FBXL14, IQSEC3, KDM5A, LINC00942, LOC574538, NINJ2, RAD52, SLC6A12, SLC6A13 and WNK1). All previous cases reported with partial monosomy of 12p13.33 are associated with neurodevelopmental delay, and we suggest that ERC1, which encodes a regulator of neurotransmitter release, is the best gene candidate contributing to this phenotype as well as to the ASD of our patient.     

De novo 3q22.1 q24 deletion associated with multiple congenital anomalies,growth retardation and intellectual disability

We describe a boy with a de novo deletion of 15.67 Mb spanning 3q22.1q24. He has bilateral micropthalmia, ptosis, cleft palate, global developmental delay and brain, skeletal and cardiac abnormalities. In addition, he has bilateral inguinal hernia and his right kidney is absent. We compare his phenotype with seven other patients with overlapping and molecularly defined interstitial 3q deletions. This patient has some phenotypic features that are not shared by the other patients. More cases with smaller deletions defined by high resolution aCGH will enable better genotype–phenotype correlations and prioritizing of candidate genes for the identification of pathways and disease mechanisms.     

De novo MECP2 disomy in a Mexican male carrying a supernumerary marker chromosome and no typical Lubs syndrome features

Xq28 duplication, including the MECP2 gene, is among the most frequently identified Xq subtelomeric rearrangements. The resulting clinical phenotype is named Lubs syndrome and mainly consists of intellectual disability, congenital hypotonia, absent speech, recurrent infections, and seizures. Here we report a Mexican male patient carrying a supernumerary marker chromosome with de novo Xq28 gain. By MLPA, duplication of MECP2, GDI1, and SLC6A8 was found and a subsequent a-CGH analysis demonstrated that the gain spanned ~ 2.1 Mb. Despite gain of the MECP2 gene, the features of this patient do not evoke Lubs syndrome. Probably the mosaicism of the supernumerary marker chromosome is modifying the phenotype in this patient.     

Chromosomal microarray analysis of consecutive individuals with autism spectrum disorders or learning disability presenting for genetic services

Chromosomal microarray analysis is now commonly used in clinical practice to identify copy number variants (CNVs) in the human genome. We report our experience with the use of the 105 K and 180 K oligonucleotide microarrays in 215 consecutive patients referred with either autism or autism spectrum disorders (ASD) or developmental delay/learning disability for genetic services at the University of Kansas Medical Center during the past 4 years (2009–2012). Of the 215 patients [140 males and 75 females (male/female ratio = 1.87); 65 with ASD and 150 with learning disability], abnormal microarray results were seen in 45 individuals (21%) with a total of 49 CNVs. Of these findings, 32 represented a known diagnostic CNV contributing to the clinical presentation and 17 represented non-diagnostic CNVs (variants of unknown significance). Thirteen patients with ASD had a total of 14 CNVs, 6 CNVs recognized as diagnostic and 8 as non-diagnostic. The most common chromosome involved in the ASD group was chromosome 15. For those with a learning disability, 32 patients had a total of 35 CNVs. Twenty-six of the 35 CNVs were classified as a known diagnostic CNV, usually a deletion (n = 20). Nine CNVs were classified as an unknown non-diagnostic CNV, usually a duplication (n = 8). For the learning disability subgroup, chromosomes 2 and 22 were most involved. Thirteen out of 65 patients (20%) with ASD had a CNV compared with 32 out of 150 patients (21%) with a learning disability. The frequency of chromosomal microarray abnormalities compared by subject group or gender was not statistically different. A higher percentage of individuals with a learning disability had clinical findings of seizures, dysmorphic features and microcephaly, but not statistically significant. While both groups contained more males than females, a significantly higher percentage of males were present in the ASD group.