Haploinsufficiency of ZNF238 is associated with corpus callosum abnormalities in 1q44 deletions

A variety of candidate genes have been proposed to cause corpus callosum abnormalities (CCAs) in patients with terminal chromosome 1q deletions. Recent data excluded AKT3 and implicated ZNF238 and/or CEP170 as genes causative of corpus callosum anomalies in patients with 1q43–1q44 deletions. We report on a girl with dysmorphic features, seizures beginning in infancy, hypotonia, marked developmental delay, and dysgenesis of the corpus callosum. Chromosomal microarray analysis detected a de novo 1.47 Mb deletion at 1q44. The deleted interval encompasses the ZNF238 gene but not the CEP170 or AKT3 genes, thus providing additional evidence for the former and against the latter as being causative of corpus callosum anomalies in patients with such deletions. © 2013 Wiley Periodicals, Inc.     

Novel deletions of 14q11.2 associated with developmental delay, cognitive impairment and similar minor anomalies in three children

METHODS AND RESULTS: We identified de novo submicroscopic chromosome 14q11.2 deletions in two children with idiopathic developmental delay and cognitive impairment. Vancouver patient 5566 has a approximately 200 kb deletion and Vancouver patient 8326 has a approximately 1.6 Mb deletion. The Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources (DECIPHER) revealed a third patient with idiopathic developmental delay and cognitive impairment, DECIPHER patient 126, who has a approximately 1.1 Mb deletion of 14q11.2. The deletion of patient 5566 overlaps that of patient 126 and both of these deletions lie entirely within that of patient 8326. All three children have similar dysmorphic features, including widely-spaced eyes, short nose with flat nasal bridge, long philtrum, prominent Cupid's bow of the upper lip, full lower lip and similar auricular anomalies. CONCLUSION: The minimal common deletion region on chromosome 14q11.2 is only approximately 35 kb (from 20.897 to 20.932, University of California at Santa Cruz (UCSC) Genome Browser; build hg18, March 2006) and includes only two genes, SUPT16H and CHD8, which are good candidate genes for the phenotypes. The non-recurrent breakpoints of these patients, the presence of normal copy number variants in the region and the local genomic structure support the notion that this region has reduced stability.     

A new microdeletion syndrome of 5q31.3 characterized by severe developmental delays, distinctive facial features, and delayed myelination

Chromosomal deletion including 5q31 is rare and only a few patients have been reported to date. We report here the first two patients with a submicroscopic deletion of 5q31.3 identified by microarray-based comparative genomic hybridization. The common clinical features of both patients were marked hypotonia,feeding difficulty in infancy, severe developmental delay, and epileptic/nonepileptic encephalopathy associated with delayed myelination. Both patients also shared characteristic facial features,including narrow forehead, low-set and dysmorphic ears, bilateral ptosis, anteverted nares, long philtrum, tented upper vermilion,edematous cheeks, and high arched palate. The deleted region contains clustered PCDHs, including PCDHA [corrected]. and PCDHG, which are highly expressed in the brain where they function to guide neurons during brain development, neuronal differentiation, and synaptogenesis. The common deletion also contains neuregulin 2(NRG2), a major gene for neurodevelopment. We suggest that 5q31.3 deletion is responsible for severe brain developmental delay and distinctive facial features, and that the common findings in these two patients should be recognized as a new microdeletion syndrome. We need further investigations to determine which genes are really responsible for patients' characteristic features     

Girl with accelerated growth, hearing loss, inner ear anomalies, delayed myelination of the brain, and del(22)(q13.1q13.2)

We report on an 18-month-old Japanese girl with 46,XX,del(22)(q13.1q13.2). To our knowledge, this is the first report of a case of interstitial deletion of a 22q13.1-q13.2 segment. Clinical features included hearing loss accompanied by inner ear anomalies, hypotonia and minor anomalies, such as a long philtrum, full eyelids, epicanthus, left transverse palmar crease and psychomotor developmental delay. Despite the chromosomal deletion, her physical growth was accelerated: her height was between the 75th and 90th percentiles for her age. Her brain MRI showed signs of delayed myelination. The three-dimensional MRI of the inner ear showed abnormalities of the cochlea and vestibule in both ears. Clinical features of the patient are similar to those of a patient with a del(22)(q13.1q13.33) karyotype previously reported by Romain et al.     

A de novo non-sense mutation in ZBTB18 in a patient with features of the 1q43q44 microdeletion syndrome

The phenotype of patients with a chromosome 1q43q44 microdeletion (OMIM; 612337) is characterized by intellectual disability with no or very limited speech, microcephaly, growth retardation, a recognizable facial phenotype, seizures, and agenesis of the corpus callosum. Comparison of patients with different microdeletions has previously identified ZBTB18 (ZNF238) as a candidate gene for the 1q43q44 microdeletion syndrome. Mutations in this gene have not yet been described. We performed exome sequencing in a patient with features of the 1q43q44 microdeletion syndrome that included short stature, microcephaly, global developmental delay, pronounced speech delay, and dysmorphic facial features. A single de novo non-sense mutation was detected, which was located in ZBTB18. This finding is consistent with an important role for haploinsufficiency of ZBTB18 in the phenotype of chromosome 1q43q44 microdeletions. The corpus callosum is abnormal in mice with a brain-specific knock-out of ZBTB18. Similarly, most (but not all) patients with the 1q43q44 microdeletion syndrome have agenesis or hypoplasia of the corpus callosum. In contrast, the patient with a ZBTB18 point mutation reported here had a structurally normal corpus callosum on brain MRI. Incomplete penetrance or haploinsufficiency of other genes from the critical region may explain the absence of corpus callosum agenesis in this patient with a ZBTB18 point mutation. The findings in this patient with a mutation in ZBTB18 will contribute to our understanding of the 1q43q44 microdeletion syndrome.     

Classical Noonan syndrome is not associated with deletions of 22q11

Deletions of 22qll cause DiGeorge sequence (DGS), velo-cardio-facial syndrome (VCFS), conotruncal anomaly face syndrome, and some isolated conotruncal heart anomalies. Demonstration of a 22qll deletion in a patient with manifestations of DGS and Noonan syndrome (NS) has raised the question of whether NS is another of the chromosome 22 microdeletion syndromes. This prompted us to evaluate a cohort of patients with NS for evidence of 22qll deletions. Five of 6 NS propositi studied in our laboratory with marker N25 (D22S75) did not have a 22qll deletion. A 2-month-old infant with several findings suggestive of NS did have a 22qll deletion, suggesting that a small number of 22qll deletion propositi may present with a NS-like picture. However, most cases of NS must have another cause. © 1995 Wiley-Liss, Inc.     

De novo 1q32q44 duplication and distal 1q trisomy syndrome

We report on an infant with minor anomalies and a de novo 1q duplication. The chromosomal abnormality was diagnosed prenatally after sonographic detection of cerebral ventriculomegaly and bilateral choroid plexus cysts in the fetus. The amniocentesis showed an abnormal male karyotype, 46,XY,dup(1)(q32q44), subsequently confirmed by fluorescence in situ hybridization using whole chromosome paint 1 and comparative genomic hybridization. The baby, born at 37 weeks of gestation, had wide cranial sutures and large fontanelles, sloping forehead, hypertelorism, short and downward-slanting palpebral fissures, a high-arched and narrow palate, malformed ears, and long feet with overriding second and third toes. This is the sixth case of known duplication involving the 1q32q44 segment; the physical findings in the case reported herein are similar to those of other patients reported previously, providing further evidence of the existence of the "distal 1q trisomy" phenotype.     

Interstitial 1q43-q43 deletion with left ventricular noncompaction myocardium

We describe a newborn infant with del(1)(q) syndrome, presenting with rare congenital cardiomyopathy and left ventricular noncompaction myocardium (LVNC), as well as typical clinical features such as facial dysmorphism and psychomotor retardation. Although conventional chromosome banding at 850 bands per haploid set indicated a karyotype of 46,XX,add(1)(q42.3), FISH analysis confirmed that the deleted portion was limited to within q43, and q44 was preserved. Therefore, the chromosome constitution is 46,XX,del(1)(q43q43), which has not previously been reported in the literature. Screening for the mutations in the candidate genes for LVNC, i.e. G4.5, CSX, Dystrobrevin, FKBP12, and Desmin, produced negative results. Interestingly, the deleted portion includes the locus for the cardiac ryanodine receptor type 2 gene (RyR2), that selectively binds to the FKBP12 homolog, FKBP12.6. The relationship between this rare myocardial abnormality and deletion of q43 is currently unknown and awaits further accumulation of cases with the same chromosomal aberration.     

Delineation of a deletion region critical for corpus callosal abnormalities in chromosome 1q43-q44

Submicroscopic deletions involving chromosome 1q43-q44 result in cognitive impairment, microcephaly, growth restriction, dysmorphic features, and variable involvement of other organ systems. A consistently observed feature in patients with this deletion are the corpus callosal abnormalities (CCAs), ranging from thinning and hypoplasia to complete agenesis. Previous studies attempting to delineate the critical region for CCAs have yielded inconsistent results. We conducted a detailed clinical and molecular characterization of seven patients with deletions of chromosome 1q43-q44. Using array comparative genomic hybridization, we mapped the size, extent, and genomic content of these deletions. Four patients had CCAs, and shared the smallest region of overlap that contains only three protein coding genes, CEP170, SDCCAG8, and ZNF238. One patient with a small deletion involving SDCCAG8 and AKT3, and another patient with an intragenic deletion of AKT3 did not have any CCA, implying that the loss of these two genes is unlikely to be the cause of CCA. CEP170 is expressed extensively in the brain, and encodes for a protein that is a component of the centrosomal complex. ZNF238 is involved in control of neuronal progenitor cells and survival of cortical neurons. Our results rule out the involvement of AKT3, and implicate CEP170 and/or ZNF238 as novel genes causative for CCA in patients with a terminal 1q deletion.