Recurrent fetal syndromic spina bifida associated with 3q26.1-qter duplication and 5p13.33-pter deletion due to familial balanced rearrangement.

OBJECTIVE: Neural tube defects belong to the second most common group of congenital anomalies, after heart defects, which can be diagnosed by prenatal ultrasonography. Rarely, neural tube defects can be associated with chromosomal abnormalities, including full and partial aneuploidies. We report a familial fetal case with syndromic spina bifida and discuss its association with partial 3q duplication and partial 5p deletion. MATERIALS AND METHODS: Clinical findings of three affected family members in two generations and two carriers of the balanced translocation are described. Conventional cytogenetic and fluorescence in situ hybridization (FISH) analysis of the carrier, as well as subtelomeric multiplex ligation-dependent probe amplification (MLPA) and array comparative genomic hybridization (CGH) analysis on the DNA extracted from affected family members was performed. RESULTS: Subtelomeric FISH analysis of the proposita revealed balanced reciprocal translocation between the long arm of chromosome 3 and short arm of chromosome 5. Subtelomeric MLPA screening of the first child revealed the deletion in 5p15.33 and duplication in 3q29 chromosomal loci, the finding consisting of the unbalanced rearrangement involving the short arm of chromosome 5 and long arm of chromosome 3. Array CGH analysis of the DNA of the second affected child revealed a 31.1Mb duplication of 3q26.1-qter and a 33.6Mb deletion of 5p13.33-pter. CONCLUSION: Our report serves to emphasize the consistency in the prenatal sonographic feature of spina bifida in consecutive pregnancies with fetuses associated with partial trisomy 3q (3q26.1-qter) and partial monosomy 5p (5p13.33-pter). The use of molecular cytogenetic technologies such as array CGH and FISH is important for clarifying any type of unbalanced chromosome rearrangement.

Clinical, cytogenetic and molecular study of a case of ring chromosome 10.

Ring chromosome 10 is a rare cytogenetic finding. Only a few cases with molecular cytogenetic definition have been reported. We report here on a child with a ring chromosome 10, which is associated with prenatal and postnatal growth retardation, microcephaly, dysmorphic features, hypotonia, heart defect, severe pes equinovarus, and bronchial asthma. The chromosomal aberration was defined by chromosome microarray analysis, which revealed two deletions at 10pter (3.68 Mb) and 10qter (4.26 Mb). The clinical features are very similar to those reported in other clinical cases with ring chromosome 10, excluding bronchial asthma, which has not been previously reported in individuals with ring chromosome 10.

Relatives with opposite chromosome constitutions, rec(10)dup(10p)inv(10)(p15.1q26.12) and rec(10)dup(10q)inv(10)(p15.1q26.12), due to a familial pericentric inversion.

Large pericentric inversions in chromosome 10 are rare chromosomal aberrations with only few cases of familial inheritance. Such chromosomal rearrangements may lead to production of unbalanced gametes. As a result of a recombination event in the inversion loop, 2 recombinants with duplicated and deficient chromosome segments, including the regions distal to the inversion, may be produced. We report on 2 relatives in a family with opposite terminal chromosomal rearrangements of chromosome 10, i.e. rec(10)dup(10p)inv(10) and rec(10)dup(10q)inv(10), due to familial pericentric inversion inv(10)(p15.1q26.12). Based on array-CGH results, we characterized the exact genomic regions involved and compared the clinical features of both patients with previous reports on similar pericentric inversions and regional differences within 10p and 10q. The fact that both products of recombination are viable indicates a potentially high recurrence risk of unbalanced offspring. This report of unbalanced rearrangements in chromosome 10 in 2 generations confirms the importance of screening for terminal imbalances in patients with idiopathic intellectual disability by molecular cytogenetic techniques such as FISH, MLPA or microarrays. It also underlines the necessity for FISH to define structural characteristics of such cryptic intrachromosomal rearrangements and the underlying cytogenetic mechanisms.

Considering specific clinical features as evidence of pathogenic copy number variants.

Since the introduction of high-resolution microarray technologies, it has become apparent that structural chromosomal rearrangements can lead to a wide variety of clinical manifestations, including developmental delay/intellectual disability (DD/ID). It has been shown previously that the diagnostic yield of genome-wide array-based identification of submicroscopic alterations in patients with ID varies widely and depends on the patient selection criteria. More attempts have recently been made to define the phenotypic clues of pathogenic copy number variants (CNVs). The aim of this study was to investigate a well-phenotyped cohort of patients with DD/ID and determine whether certain clinical features may serve as indicators for pathogenic CNVs. A retrospective analysis was conducted for patients with DD/ID (n = 211) who were tested using genome-wide chromosomal microarray technologies and a review of the clinical data was performed. Pathogenic CNVs were detected in 29 patients. In comparison with individuals who had normal molecular karyotyping results (n = 182), malformations of the musculoskeletal system; congenital malformations of the CNS (particularly hydrocephalus and congenital malformations of the corpus callosum); minor anomalies of the eye, face, and neck subgroup (particularly downward-slanting palpebral fissures, minor anomalies of the ear, and micrognathia); brachydactyly; and umbilical hernia were more common in patients with chromosomal alterations. A multivariate logistic regression analysis allowed the identification of three independent pathogenic CNV predictors: congenital malformations of the corpus callosum, minor anomalies of the ear, and brachydactyly. Insights into the chromosomal phenotype may help to increase the diagnostic yield of microarray technologies and sharpen the distinction between chromosomal alterations and other conditions.

Familial distal monosomy 5p15.3-pter with trisomy 12q24.2-qter resulting in neurodevelopmental delay and dysmorphic features.

Developmental delay and brain anomalies leading to significant morbidity and mortality are frequently caused by chromosomal rearrangements. We report on a familial unbalanced translocation resulting in distal monosomy 5p15.3-pter with trisomy 12q24.2-qter in 2 half siblings with cerebral dysgenesis, severe intellectual disability, dysmorphic features, progressive weakness, and atrophy of muscles.

A new single gene deletion on 2q34: ERBB4 is associated with intellectual disability.

We report on a 15-year-old patient with hyperactivity, intellectual disability and severe speech developmental delay. An array CGH analysis revealed de novo 2q34 deletion, 958 kb in size, involving a single protein coding gene ERBB4 (position 212,505,294-213,463,152; NCBI build 36). The ERBB4 gene is important in numerous neurobiological processes in both the developing and the adult brain. The NRG1-ERBB4 signaling pathway has been recently implicated in the pathophysiology of schizophrenia and epilepsy. Many risk haplotypes were identified in several studies across different populations. The severe clinical consequences in our patient demonstrate that the haploinsufficiency of ERBB4 is crucial for intellectual and cognitive function. These observations are compatible with previously reported results.

Clinical and molecular characterization of a second case of 7p22.1 microduplication.

The use of high-resolution microarray technology for investigation of patients with intellectual disability and/or congenital anomalies provided the unique possibility to identify new microdeletion/microduplication syndromes and discover the dosage sensitive genes, which are implicated in the manifestation of various genetic conditions. Microduplication of the 7p22.1 region, 1.7 Mb in size, has very recently been reported, representing the smallest interstitional 7p duplication, associated with specific facial features and speech delay. We report on a patient with an even smaller 7p22.1 de novo microduplication, 1 Mb in size, detected in a 14.5-year-old patient with mild intellectual disability and similar facial dysmorphism, including macrocephaly, ocular hypertelorism, low-set ears, and other features. There are 15 RefSeq genes included in this duplication. ACTB gene is a strong candidate gene for the alteration of craniofacial development. Further cases with similar duplications will contribute to the delineation of a potential new microduplication syndrome of 7p22.1.

A single gene deletion on 4q28.3: PCDH18--a new candidate gene for intellectual disability?

We report a boy with severe developmental delay, seizures, microcephaly, hypoplastic corpus callosum, internal hydrocephalus and dysmorphic features (narrow forehead, round face, deep-set eyes, blue sclerae, large and prominent ears, nose with anteverted nares, thin upper lip, small and wide-spaced teeth, hyperextensibility of the elbows, wrists, and fingers, fingertip pads, broad hallux, sacral dimple), carrying a 1.53 Mb interstitial deletion at 4q28.3. The deletion was detected by Agilent 105K oligo-array genome hybridization and involves the genomic region between 137,417,338 and 138,947,282 base pairs on chromosome 4 (NCBI build 36). The alteration was inherited from a healthy mother and contains a single gene, PCDH18 which encodes a cadherin-related neuronal receptor thought to play a role in the establishment and function of cell-cell connections in the brain. Thus, haploinsufficiency of this gene may contribute to altered brain development and associated malformations. We found that this deletion is a private inherited copy number variation that is associated with specific clinical findings in our patient and propose the PCDH18 gene as a possible candidate gene for intellectual disability.

De novo 5q35.5 duplication with clinical presentation of Sotos syndrome.

We report on a girl with developmental delay and a de novo 264 kb interstitial duplication in the region of Sotos syndrome at 5q35.3 in the immediate vicinity of critical NSD1 gene, but manifesting the phenotype, of overgrowth both prenatal stage and postnatal, macrocephaly, developmental delay, and resembling that of Sotos syndrome, rather than the recently reported syndrome of reciprocal duplication. The duplication is located right downstream from the NSD1 gene, a region which appears critical for the expression of the gene as regulatory elements might be disrupted or the expression of a not amplified critical gene might be otherwise affected by the duplicated region. Thus,in the process of evaluating identified CNVs attention should be drawn to the possible influence of chromosomal rearrangement on distant genes, which could add additional diversity to genomic disorders. Our case demonstrates that evaluation of the size of chromosomal alteration and gene content are not sufficient for assessment of CNV's pathogenicity and the context of adjacent genes should be considered.