Clinical comparison of 10q26 overlapping deletions: delineating the critical region for urogenital anomalies.

The 10q26 deletion syndrome is a clinically heterogeneous disorder. The most common phenotypic characteristics include pre- and/or postnatal growth retardation, microcephaly, developmental delay/intellectual disability and a facial appearance consisting of a broad nasal bridge with a prominent nose, low-set malformed ears, strabismus, and a thin vermilion of the upper lip. In addition, limb and cardiac anomalies as well as urogenital anomalies are occasionally observed. In this report, we describe three unrelated females with 10q26 terminal deletions who shared clinical features of the syndrome, including urogenital defects. Cytogenetic studies showed an apparently de novo isolated deletion of the long arm of chromosome 10, with breakpoints in 10q26.1, and subsequent oligo array-CGH analysis confirmed the terminal location and defined the size of the overlapping deletions as ∼ 13.46, ∼ 9.31 and ∼ 9.17 Mb. We compared the phenotypic characteristics of the present patients with others reported to have isolated deletions and we suggest that small 10q26.2 terminal deletions may be associated with growth retardation, developmental delay/intellectual disability, craniofacial features and external genital anomalies whereas longer terminal deletions affecting the 10q26.12 and/or 10q26.13 regions may be responsible for renal/urinary tract anomalies. We propose that the haploinsufficiency of one or several genes located in the 10q26.12-q26.13 region may contribute to the renal or urinary tract pathogenesis and we highlight the importance of FGFR2 and probably of CTBP2 as candidate genes.

Array CGH detection of a novel cryptic deletion at 3q13 in a complex chromosome rearrangement.

Complex chromosome rearrangements (CCRs) are extremely rare in humans. About 20% of the apparently balanced CCRs have an abnormal phenotype and the degree of severity correlates with a higher number of breakpoints. Several studies using FISH and microarray technologies have shown that deletions in the breakpoints are common although duplications, insertions and inversions have also been detected. We report a patient with two simultaneous reciprocal translocations, t(3;4) and t(2;14;18), involving five chromosomes and six breakpoints. He showed dysmorphic features, preaxial polydactyly in the left hand, brachydactyly, postnatal growth retardation and developmental delay. The rearrangement was characterized by FISH analysis which detected an interstitial segment from chromosome 14 inserted in the derivative chromosome 2, and by whole genome array which revealed an interstitial deletion of approximately 4.5 Mb at the breakpoint site on chromosome 3. To our knowledge this microdeletion has not been previously reported and includes ~12 genes. The haploinsufficiency of one or several of these genes is likely to have contributed to the clinical phenotype of the patient.

Pre- and postnatal findings in a patient with a novel rec(8)dup(8q)inv(8)(p23.2q22.3) associated with San Luis Valley syndrome.

San Luis Valley syndrome, which is due to a recombinant chromosome 8 (SLV Rec8) found in Hispanic individuals from Southwestern United States, is a well-established syndrome associated with intellectual disabilities and, frequently, severe cardiac anomalies. We report for the first time on a Moroccan girl with a recombinant chromosome 8 prenatally diagnosed as SLV Rec8 by conventional cytogenetic studies. At birth, an oligo array-CGH (105 K) defined the breakpoints and the size of the imbalanced segments, with a deletion of ≈ 2.27 Mb (8p23.2-pter) and a duplication of ≈ 41.93 Mb (8q22.3-qter); thus this recombinant chromosome 8 differed from that previously reported in SLV Rec8 syndrome. The phenotypic characteristics associated with this SLV Rec8 genotype overlap those commonly found in patients with 8q duplication reported in the literature. We review SLV Rec8 and other chromosome 8 aberrations and suggest that the overexpression of cardiogenic genes located at 8q may be the cause of the cardiac defects in this patient.

Rapp-Hodgkin syndrome and SHFM1 patients: delineating the p63-Dlx5/Dlx6 pathway.

Rapp-Hodgkin Syndrome (RHS) is a genetic disorder resulting from mutations in the TP63 gene encoding p63 transcription factor. p63 is directly associated with a cis-regulatory element on chromosome 7q21 that controls the expression of DLX5 and DLX6 genes which are involved in craniofacial abnormalities and ectrodactyly or split hand/foot malformation (SHFM). Chromosomal deletions on 7q21 locus can result in loss of DXL5/DLX6 and/or in loss/disruption of cis-regulatory elements, at which p63 binds. We report two patients that have in common a p63-Dlx5/Dlx6 pathway dysregulation. One showed growth retardation, craniofacial dysmorphism, syndactyly, developmental delay and a de novo deletion (~8.5Mb) on chromosome 7q21.13-q21.3, including DLX5 and DLX6. The second patient with a clinical diagnosis of RHS showed a de novo heterozygous missense mutation, c. 401G>A (p.G134D), in TP63 (exon 4). Our findings may contribute to a greater understanding of the pathogenic mechanisms underlying disorders caused by TP63 mutations.

Molecular characterization of a new patient with a non-recurrent inv dup del 2q and review of the mechanisms for this rearrangement.

We report on newborn baby with microcephaly, facial anomalies, congenital heart defects, hypotonia, wrist contractures, long fingers, adducted thumbs, and club feet. Cytogenetic studies revealed an inverted duplication with terminal deletion (inv dup del) of 2q in the patient and a paternal 2qter deletion polymorphism. Microsatellite markers demonstrated that the inv dup del was maternal in origin and intrachromosomal. Intra or interchromosomal rearrangements may cause this aberration either by a U-type exchange (end-to-end fusion), an unequal crossover between inverted repeats (non-allelic homologous recombination: NAHR), or through breakage-fusion-bridge (BFB) cycles leading to a sister chromatid fusion by non-homologous end joining (NHEJ). A high-resolution oligo array-CGH (244 K) defined the breakpoints and did not detect a single copy region with a size exceeding 12.93 Kb in the fusion site. The size of the duplicated segment was 38.75 Mb, extending from 2q33.1 to 2q37.3 and the size of the terminal deletion was 2.85 Mb in 2q37.3. Our results indicate that the inv dup del (2q) is likely a non-recurrent chromosomal rearrangement generated by a NHEJ mechanism. The major clinical characteristics associated with this 2q rearrangement overlap with those commonly found in patients with 2q duplication reported in the literature.

Characterization of a de novo complex chromosomal rearrangement in a patient with cri-du-chat and trisomy 5p syndromes.

Two syndromes with abnormalities of the short arm of chromosome 5 have been described: cri-du-chat (resulting from 5p deletion) and trisomy 5p. We report for the first time a patient with both syndromes, resulting from a complex chromosomal rearrangement with an inverted duplication of 5p13.1-p14.2, a deletion of 5p14.2-pter, and a duplication of 5p12, characterized by array-CGH and BAC clones. The patient showed phenotypic characteristics of both syndromes and died at 3 months of age as a result of cardiorespiratory failure, probably associated with the clinical severity of the trisomy 5p syndrome. We propose a potential causative mechanism for this rearrangement.

Intrachromosomal partial triplication of chromosome 13 secondary to a paternal duplication with mild phenotypic effect.

Intrachromosomal triplications are rare and can be mistaken for duplications. The majority of triplications reported are de novo, mostly involving chromosome 15q, and have a middle inverted repeat. We report on the clinical, cytogenetic, and molecular analyses of a patient with a novel triplication 13q21.1-q21.33 secondary to a familial duplication 13q21.1-q21.33 with mild phenotypic effect in three generations. The propositus was an 8-year-old boy referred because of language delay and mild mental retardation. His weight, height and OFC were above the 97th centile. He had delayed tooth eruption and subtle dysmorphic features. Chromosome analysis (550 band stage) showed extra material in 13q21. Family history was unremarkable except for adult-onset sensorineural hearing loss in the father and paternal grandfather. Their karyotypes and those of both brothers of the propositus also showed an abnormal chromosome 13 but with less extra genetic material. FISH analysis with several BAC clones showed a triplication in the propositus between 204N9 and 184B18 (which mapped to 13q21.1 and 13q21.33, respectively) and a direct duplication for the same fragment (around 12 Mb) in the rest of the family members with the abnormal chromosome 13. The FISH signals did not show a middle inverted repeat. We describe the first intrachromosomal triplication 13q21.1-q21.33 derived from a paternal duplication. Meiotic instability in the transmission of a duplication has not been previously observed. Phenotypic variability may be explained by chromosomal non-penetrance or dosage critical loci located in the triplicate/duplicate segment.