Elyes Chabchoub

Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome

3MC syndrome has been proposed as a unifying term encompassing the overlapping Carnevale, Mingarelli, Malpuech and Michels syndromes. These rare autosomal recessive disorders exhibit a spectrum of developmental features, including characteristic facial dysmorphism, cleft lip and/or palate, craniosynostosis, learning disability and genital, limb and vesicorenal anomalies. Here we studied 11 families with 3MC syndrome and identified two mutated genes, COLEC11 and MASP1, both of which encode proteins in the lectin complement pathway (collectin kidney 1 (CL-K1) and MASP-1 and MASP-3, respectively). CL-K1 is highly expressed in embryonic murine craniofacial cartilage, heart, bronchi, kidney and vertebral bodies. Zebrafish morphants for either gene develop pigmentary defects and severe craniofacial abnormalities. Finally, we show that CL-K1 serves as a guidance cue for neural crest cell migration. Together, these findings demonstrate a role for complement pathway factors in fundamental developmental processes and in the etiology of 3MC syndrome.

The facial dysmorphy in the newly recognised microdeletion 2p15–p16.1 refined to a 570 kb region in 2p15

In this journal, Rajcan-Separovic et al 1 characterised a new microdeletion syndrome involving chromosome 2p15–16.1 in two patients with an autistic disorder (AD) and multiple congenital anomalies (MCA) with recognisable dysmorphic features. While screening for genomic copy number variations with a 1 Mb resolution bacterial artificial chromosome (BAC) array-based comparative genomic hybridisation (aCGH) in patients referred for the aetiological diagnosis of mental retardation and MCA (MR/MCA), a 570 kb de novo microdeletion at 2p15 was detected. We compare our findings with those of Rajcan-Separovic et al 1 and we discuss the phenotype–genotype correlations. The patient is a 16-year-old boy born to healthy and non-consanguineous Belgian parents. He was first referred at the age of 9½ years (fig 1A) for school difficulties secondary to mild mental retardation (IQ of 50), MCA with ectomorphic habitus (height 147 cm (>P97), weight 25.7 kg (P3) and a normal occipito-frontal circumference of 54.2 cm). He has characteristic dysmorphic features including high forehead, fine hair, telecanthus, antimongoloid palpebral fissures, large ears, broad and high nasal root with prominent tip, high palate with nasal speech, everted lower lip, long fingers, pectus excavatum, kyphoscoliosis (>20°), congenital heart defect consisting of a bicuspid aortic valve with mild aortic valve insufficiency without stenosis and a prolapsed mitral valve with a first grade mitral …

Molecular characterisation of a mosaicism with a complex chromosome rearrangement: evidence for coincident chromosome healing by telomere capture and neo-telomere formation

Background: Broken chromosomes must acquire new telomeric “caps” to be structurally stable. Chromosome healing can be mediated either by telomerase through neo-telomere synthesis or by telomere capture. Aim: To unravel the mechanism(s) generating complex chromosomal mosaicisms and healing broken chromosomes. Methods: G banding, array comparative genomic hybridization (aCGH), fluorescence in-situ hybridisation (FISH) and short tandem repeat analysis (STR) was performed on a girl presenting with mental retardation, facial dysmorphism, urogenital malformations and limb anomalies carrying a complex chromosomal mosaicism. Results & discussion: The karyotype showed a de novo chromosome rearrangement with two cell lines: one cell line with a deletion 9pter and one cell line carrying an inverted duplication 9p and a non-reciprocal translocation 5pter fragment. aCGH, FISH and STR analysis enabled the deduction of the most likely sequence of events generating this complex mosaic. During embryogenesis, a double-strand break occurred on the paternal chromosome 9. Following mitotic separation of both broken sister chromatids, one acquired a telomere vianeo-telomere formation, while the other generated a dicentric chromosome which underwent breakage during anaphase, giving rise to the del inv dup(9) that was subsequently healed by chromosome 5 telomere capture. Conclusion: Broken chromosomes can coincidently be rescued by both telomere capture and neo-telomere synthesis.

Submicroscopic distal deletion of the long arm of chromosome 13(13q34) with corpus callosum agenesis

The 13q deletion syndrome phenotype was first described in 1969 [Allderdice et al., 1969] and comprises developmental delay, growth retardation, microcephaly, hypertelorism, a broad nasal bridge, micrognathia, hypoplastic or absent thumbs, hypoplastic kidneys, and ambiguous genitalia. Described central nervous system (CNS) anomalies are various comprising neural tube defects, holoprosencephaly, Dandy–Walker malformation and agenesis of the corpus callosum. The phenotypic description of the 13qsyndrome is thought to be dependent on the location and size of the deleted segment. Previously 13q deletions were assigned to three groups: Group 1 (deletions proximal to the presumed ‘‘critical region’’ q32 [Brown et al., 1995]) with growth deficiency, mild mental retardation and minor anomalies; Group 2 (deletions containing q32) with the most serious phenotype with growth deficiency, severe mental retardation, microcephaly, dysmorphic facies, gastrointestinal malformations, distal limb deficiencies and CNS malformations. The zinc finger protein of cerebellum 2 (ZIC2) gene maps to the 13q32.3 region and has been considered a candidate for CNS anomalies [Brown et al., 1995]; Group 3 (terminal deletions q33-34) with mental retardation but lack of major malformations and growth deficiency [Brown et al., 1995; Luo et al., 2000]. We report on a boy with a terminal 13q34 deletion with agenesis of the corpus callosum. A non-consanguineous couple was already prenatally followed in the second pregnancy because of fetal colpocephaly with suspicion of agenesis of the corpus callosum with normal prenatal karyotype 46,XY. He was born at 37 weeks (weight: 2,500 g; length: 48 cm; and head circumference: 34 cm). The diagnosis of agenesis of the corpus callosum was confirmed by ultrasound and MRI. Mental development was first evaluated at the age of 3 years with the Snijders-Oomen non-verbal intelligence test (SON-R test) [Snijders and Snijders-Oomen, 1958] and was normal. At age 6 years a Bayley developmental scale was done and resulted in a borderline intelligence (total IQ: 72; verbal IQ: 92; performance IQ: 59). At age 8 years his weight, length and head circumference were at the 50th centile. A repeat MRI confirmed agenesis of the corpus callosum without associated migration anomalies. At the age of 10 years he was not dysmorphic, and had sociable behavior but delayed motor skills. He was in a special school for Specific Learning Disabilities. Conventional karyotype is normal. A 1 Mb resolution BAC array comparative genomic hybridization (aCGH) shows a 4.4 Mb deletion of 13q34 between the flanking clones RP11-40E6 and RP11 -245B11 (Fig. 1a). Fluorescence in situ hybridization with probe RP11-310D8 confirmed the 13q34 deletion (Fig. 1b) that is de novo. The karyotype is 46,XY arr cgh13q34(RP11-17E4!RP11265C7) 1. Ballarati et al. [2007] reported molecular-cytogenetic characterization of 13q deletions in 14 patients confirming that those lacking the 13q32 band are more seriously affected. Two patients presenting a terminal 13q deletion but with involvement of 13q32 had agenesis of the corpus callosum and associated anomalies. Hindryckx et al. [2008] recently reported a first trimester prenatal diagnosis of 13qsyndrome with increased nuchal translucency, Dandy–Walker malformation and a small parietal encephalocele with a 13q deletion involving 13q32 (del(13)(q31.1q33.1)). But Luo et al. [2000] described a boy with a terminal 13q33-34 deletion and a lumbosacral myelomeningocele suggesting that haploinsufficiency of one or more genes mapping to 13q33-34 may be responsible for CNS malformation. The boy here is the first reported with a deletion distal to 13q32 (13q34) and agenesis of the corpus callosum as the sole major How to Cite this Article: Witters I, Chabchoub E, Vermeesch JR, Fryns J-P. 2009. Submicroscopic distal deletion of the long arm of chromosome 13(13q34) with corpus callosum agenesis.

Detection of an unusual 17p13.3 microdeletion by array comparative genomic hybridisation in a patient with lissencephaly

To the Editor: The term lissencephaly (LIS) [MIM #607432], literally meaning smooth’ brain, refers to rare malformations with reduced gyration of the cerebral cortex (1). It is the result of defective neuronal migration occurring between weeks 12 and 16 of fetal development. Children with LIS have swallowing and feeding difficulties, severe seizures and psychomotor delay and sometimes dystonia. Brain magnetic resonance imaging (MRI) shows a thickened cortex (10–20 mm), and on microscopy, four rather than six layers are seen (2). LIS variants are characterized by extra-cortical anomalies including total or partial agenesis of the corpus callosum and severe cerebellar hypoplasia, mainly of the vermis (3). Five genes have been identified that cause or contribute to LIS in humans: LIS1 (17p13.3) (4), 14-3-3e (17p13.3) (5), DCX (Xq22.3-23) (6, 7), RELN (7q22) (8), and ARX (Xp22.13) (9). We report a female patient with isolated LIS and an unusual deletion of the LIS1 gene. She was born at term to healthy non-related parents after a normal pregnancy. There was no family history of developmental or neurological disorders. From early childhood, she developed severe epilepsy and psychomotor delay. She never learned to talk or walk and is a wheelchair user. General physical examination showed a narrow forehead, a high nasal bridge, a short upper lip and a small mouth with downturned corners (Fig. 1a). Her head circumference was below the 3rd centile. Brain MRI showed LIS grade 3 with agyria of the occipital lobes transitioning to pachygyria anteriorly, with a cell-sparse layer most prominent posteriorly. In addition, there was a mild dilation of the posterior horns of the lateral ventricles (10). High-resolution G-banding karyotype and fluorescence in situ hybridisation (FISH) investigations carried out using the Smith–Magenis/ Miller–Dieker diagnostic dual commercial probe (Cytocell LPU077, Cytocell Technologies Ltd, Cambridge, UK) were normal. Subsequent sequencing of the LIS1 and DCX genes did not show any mutation. Using array comparative genomic hybridisation (CGH) at a 1 Mb resolution as previously described (11, 12), we detected a deletion of BAC clone RP11-135N5 in the Miller–Dieker syndrome (MDS) critical region on chromosome 17p13.3 (Fig. 1b). This deletion encompasses the 5#UTR and exons 1 and 2 of the LIS1 gene. Subsequent FISH analysis using the RP11-135N5 clone confirmed the deletion of maximal size 1.4 Mb on one chromosome 17 (Fig. 1c). Neither parent had the deletion. Subsequent screening with the RP11-135N5 probe of 15 patients with the same clinical condition (LIS without a microdeletion, using the commercial FISH probe, and with no mutation in LIS1 or DCX) did not detect this deletion. In comparison with the case reported by Cardoso et al. (13), the deletion in our patient is much smaller and does not extend further towards the telomere of chromosome 17p. Patients with MDS have more severe LIS, suggesting that other genes distal to LIS1 might be involved in brain development and in producing the characteristic MDS dysmorphism (1, 4, 14). Toyo-oka et al. (5) found the 14-3-3e gene to be the best candidate for the more pronounced phenotype in MDS by demonstrating that mice compound heterozygous for 14-3-3e and LIS1 show more severe defects of neuronal migration than either heterozygous mutant mouse alone. The small deleted region in this patient does not encompass the 14-3-3e gene and could explain the milder phenotype of isolated LIS. The atypical deletion found probably represents a sporadic finding because it was not found in 15 other patients with the same clinical

Oculocerebral Hypopigmentation Syndrome Maps to Chromosome 3q27.1q29

Background: In 1967, Cross et al. [J Pediatr 1967;70:398–406] reported four siblings with intellectual disability, microcephaly, neurologic and ocular disorders, and hypopigmentation involving skin and hair. This novel entity, known as oculocerebral hypopigmentation syndrome (OCHS) or Cross syndrome (OMIM 257800), is assumed to be autosomal recessive. However, its genetic cause is still unknown. Case Report: A 4-year-old girl is reported with OCHS, a history of recurrent infections and vertebral fusion of L4–L5. Central nervous system and cardiac imaging as well as metabolic screening were normal. Microscopic hair investigations did not show any melanin deposit defects. Results: Using molecular cytogenetics, we detected a de novo interstitial del(3)(q27.1q29) of the paternal chromosome. To our knowledge, this is the first molecular genetics finding in a patient with OCHS. Here we discuss the genotype-phenotype correlations and suggest candidate genes for this disorder. Conclusion: Investigating further patients would enable fine-mapping the OCHS locus and identifying its putative gene.