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Facial phenotype of 2 Kabuki-like (A:KS2; B:KS14) and 2 Kabuki patients (C:KS7; D:KS12). Note that KS2 and KS14 also show some features characteristic of the 2q37 deletion.
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Kabuki syndrome (KS) is a multiple congenital anomaly syndrome characterized by specific facial features, mild to moderate mental retardation, postnatal growth delay, skeletal abnormalities, and unusual dermatoglyphic patterns with prominent fingertip pads. A 3.5 Mb duplication at 8p23.1-p22 was once reported as a specific alteration in KS but has...
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The underlying causes of mental retardation remain unknown in about half the cases. Recent array-CGH studies demonstrated cryptic imbalances in about 25% of patients previously thought to be chromosomally normal.
Array-CGH with approximately 3500 large insert clones spaced at approximately 1 Mb intervals was used to investigate DNA copy number chan...
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... Minor variants such as brachidactyly, clinodactyly, and joint laxity, included among diagnostic criteria, are actually quite nonspecific. On the other hand, persistent foetal fingertip (100% of present cases) is a very peculiar feature, even if not pathognomonic, since other syndromes share this feature (Pitt-Hopkins syndrome, FG Opitz-Kaveggia, 2q37 microdeletion, and fetal alcohol syndrome ) [39][40][41][42]. ...
Kabuki syndrome (KS) is a well-recognized disorder characterized by postnatal growth deficiency, dysmorphic facial features, skeletal anomalies, and intellectual disability. The syndrome is caused by KMT2D gene mutations or less frequently KDM6A gene mutations or deletions. We report a systematic evaluation of KS patients from Campania region of Italy; data were also compared with literature ones. We collected data of 15 subjects (8 males and 7 females with age range 10–26 years; mean age 16.9 years) with confirmed diagnosis of KS, representing the entire cohort of patients from Campania Region. Each patient performed biochemical testing and instrumental investigation. Neuro-intellectual development, cranio-facial dysmorphisms, and multisystem involvement data were collected retrospectively. For each category, type of defects and frequency of the anomalies were analyzed. Our observation shows that KS patients from Campania region have some particular and previously underscored, neurological and immunological findings. We found high prevalence of EEG’s abnormalities (43%) and MRI brain abnormalities (60%). Microcephaly resulted more common in our series (33%), if compared with major cohorts described in literature. Biochemical features of immunodeficiency and autoimmune diseases including thyroid autoimmunity, polyserositis, and vitiligo were observed with high prevalence (54.5%). Low immunoglobulins levels were a frequent finding. Lymphocyte class investigation showed significantly reduced CD8 levels in one patient.
Conclusions : These data confirm great heterogeneity of clinical manifestations in KS and suggest to introduce further clinical diagnostic criteria in order to perform a correct and precocious diagnosis. What is Known • Kabuki syndrome is characterized by growth deficiency, dysmorphic facial features, skeletal anomalies, and intellectual disability • Immune dysfunction is a common finding but autoimmune diseases are rarely seen • Neurological features are common
What is New • Some particular facial features could help gestalt diagnosis (hypertelorism, broad nasal bridge, micrognathia, tooth agenesis, cutaneous haemangiomas and strabismus) • Higher prevalence of autoimmune disorders than previously reported • Particular neurological features are present in this cohort (EEG and MRI brain abnormalities)
... The identified chromosomal abnormalities are numerous. They can be gonosomal (mosaic 45X-47XXX , X ring) [28,29], multiple autosomal (trisomy 10p, deletion or duplication in 2q37 [30,31]). The multiple rearrangements of 8p22-8p23,1 duplication region, triplication, paracentric inversion are frequently reported in the literature [32,33], but comparative genomic hybridization techniques have not only confirmed this [34] approach. ...
... 3 KS has an estimated incidence of 1 in 32 000, and B500 cases have been reported worldwide. [4][5][6][7] The majority of cases of KS are sporadic, and the sex ratio is nearly equal. 8 In 2010, KMT2D (previously known as MLL2, NM_003482.3) ...
Kabuki syndrome (KS) (OMIM#147920) is a multiple congenital anomaly/mental retardation syndrome. Recently, pathogenic variants in KMT2D and KDM6A were identified as the causes of KS in 55.8-80.0% of patients. To elucidate further the molecular characteristics of Korean patients with KS, we screened a cohort of patients with clinically defined KS for mutations in KMT2D and KDM6A. Whole-exome sequencing and direct sequencing for validation were performed in 12 patients with a clinical suspicion of KS. KMT2D and KDM6A mutations were identified in 11 (91.7%) patients. No recurrent mutation was observed, and 10 out of the 11 mutations found were novel. KMT2D mutations were detected in 10 patients, including four small deletions or insertions and four nonsense and two missense mutations. One girl had a novel splice-site mutation in KDM6A. Each patient had a unique individual mutation. This is the first report of mutational analysis via exome sequencing in Korean patients with KS. Because the mutation-detection rate was high in this study, rigorous mutation analysis of KMT2D and KDM6A may be an important tool for the early diagnosis and genetic counseling of Korean patients with KS.Journal of Human Genetics advance online publication, 17 April 2014; doi:10.1038/jhg.2014.25.
... Six of our inverted duplications arose on chromosome 18q and were part of the Heard study, two inverted duplications arose on chromosome 2q, and one occurred on chromosome 5p. Other studies have described maternal and paternal origins of inverted duplications [4,8,60,61,62,63,64,65]. These data argue against a parent-of-origin bias for inverted duplications overall. ...
Inverted duplications are a common type of copy number variation (CNV) in germline and somatic genomes. Large duplications that include many genes can lead to both neurodevelopmental phenotypes in children and gene amplifications in tumors. There are several models for inverted duplication formation, most of which include a dicentric chromosome intermediate followed by breakage-fusion-bridge (BFB) cycles, but the mechanisms that give rise to the inverted dicentric chromosome in most inverted duplications remain unknown. Here we have combined high-resolution array CGH, custom sequence capture, next-generation sequencing, and long-range PCR to analyze the breakpoints of 50 nonrecurrent inverted duplications in patients with intellectual disability, autism, and congenital anomalies. For half of the rearrangements in our study, we sequenced at least one breakpoint junction. Sequence analysis of breakpoint junctions reveals a normal-copy disomic spacer between inverted and non-inverted copies of the duplication. Further, short inverted sequences are present at the boundary of the disomic spacer and the inverted duplication. These data support a mechanism of inverted duplication formation whereby a chromosome with a double-strand break intrastrand pairs with itself to form a "fold-back" intermediate that, after DNA replication, produces a dicentric inverted chromosome with a disomic spacer corresponding to the site of the fold-back loop. This process can lead to inverted duplications adjacent to terminal deletions, inverted duplications juxtaposed to translocations, and inverted duplication ring chromosomes.
... Six of our inverted duplications arose on chromosome 18q and were part of the Heard study, two inverted duplications arose on chromosome 2q, and one occurred on chromosome 5p. Other studies have described maternal and paternal origins of inverted duplications [4,8,60,61,62,63,64,65]. These data argue against a parent-of-origin bias for inverted duplications overall. ...
Inverted duplications are a common type of copy number variation (CNV) in germline and somatic genomes. Large duplications that include many genes can lead to both neurodevelopmental phenotypes in children and gene amplifications in tumors. There are several models for inverted duplication formation, most of which include a dicentric chromosome intermediate followed by breakage-fusion-bridge (BFB) cycles, but the mechanisms that give rise to the inverted dicentric chromosome in most inverted duplications remain unknown. Here we have combined high-resolution array CGH, custom sequence capture, next-generation sequencing, and long-range PCR to analyze the breakpoints of 50 nonrecurrent inverted duplications in patients with intellectual disability, autism, and congenital anomalies. For half of the rearrangements in our study, we sequenced at least one breakpoint junction. Sequence analysis of breakpoint junctions reveals a normal-copy disomic spacer between inverted and non-inverted copies of the duplication. Further, short inverted sequences are present at the boundary of the disomic spacer and the inverted duplication. These data support a mechanism of inverted duplication formation whereby a chromosome with a double-strand break intrastrand pairs with itself to form a ''fold-back'' intermediate that, after DNA replication, produces a dicentric inverted chromosome with a disomic spacer corresponding to the site of the fold-back loop. This process can lead to inverted duplications adjacent to terminal deletions, inverted duplications juxtaposed to translocations, and inverted duplication ring chromosomes.
... All MLPA reactions were analyzed on an ABI PRISM 3100 Genetic analyzer according to manufacturers' instructions. Each MLPA signal was normalized and compared to the corresponding peak height obtained in control samples [32,33]. ...
... Samples were hybridized onto a BAC aCGH containing 5,600 clones with a backbone mean coverage of ,1 Mb and increased density in hotspot regions for genomic rearrangements (subtelomeres, pericentromeres and regions flanked by segmental duplications). Analyses of BAC-aCGH data were performed as previously described [32]. A total of 25 samples were also studied by using an oligonucleotide Agilent H244K aCGH. ...
Congenital malformations are present in approximately 2-3% of liveborn babies and 20% of stillborn fetuses. The mechanisms underlying the majority of sporadic and isolated congenital malformations are poorly understood, although it is hypothesized that the accumulation of rare genetic, genomic and epigenetic variants converge to deregulate developmental networks.
We selected samples from 95 fetuses with congenital malformations not ascribed to a specific syndrome (68 with isolated malformations, 27 with multiple malformations). Karyotyping and Multiplex Ligation-dependent Probe Amplification (MLPA) discarded recurrent genomic and cytogenetic rearrangements. DNA extracted from the affected tissue (46%) or from lung or liver (54%) was analyzed by molecular karyotyping. Validations and inheritance were obtained by MLPA. We identified 22 rare copy number variants (CNV) [>100 kb, either absent (n = 7) or very uncommon (n = 15, <1/2,000) in the control population] in 20/95 fetuses with congenital malformations (21%), including 11 deletions and 11 duplications. One of the 9 tested rearrangements was de novo while the remaining were inherited from a healthy parent. The highest frequency was observed in fetuses with heart hypoplasia (8/17, 62.5%), with two events previously related with the phenotype. Double events hitting candidate genes were detected in two samples with brain malformations. Globally, the burden of deletions was significantly higher in fetuses with malformations compared to controls.
Our data reveal a significant contribution of rare deletion-type CNV, mostly inherited but also de novo, to human congenital malformations, especially heart hypoplasia, and reinforce the hypothesis of a multifactorial etiology in most cases.
... en casos con fisura palatina 13 . Alteraciones tipo duplicaciones en 8p22/8p23.1 encontradas en algunos pacientes 14,15 no han sido descritas posteriormente 8,16,17 . Recientemente, se han referido mutaciones del gen MLL2 como una de las principales causas en pacientes con el síndrome; este estudio se ha llevado a cabo mediante una técnica novedosa aplicada en clínica: el análisis del exoma 18 . ...
... y persistencia de almohadilla en los pulpejos de los dedos; la mayoría de estos están presentes en los pacientes descritos en este artículo. Por otro lado, hay anomalías en diferentes sistemas que se presentan con menor frecuencia pero que deben descartarse en todo paciente con diagnóstico clínico de síndrome de Kabuki, dentro de las cuales están: malformaciones del sistema cardiovascular y genitourinario como lo refieren varios de los casos previamente publicados 10,17,19,20 . El cariotipo de bandas G de alta resolución suele ser normal en la mayoría de los casos. ...
Introduction: Kabuki syndrome (OMIM: #147 920) presents as large palpebral fissures with eversion of the lateral third of the lower eyelids, depressed nasal bridge, arched eyebrows, dysplastic ears and in most cases, with mental retardation. Patients have minor and major abnormalities in different systems. Its genetic basis is heterogeneous, but recently has been associated with mutations in gen MLL2.Case reports: We present two patients with clinical features compatibles with the syndrome, mainly: large palpebral fissures with eversion of the lateral third of the lower eyelids, depressed nasal bridge, arched eyebrows, flat nose, persistent fingertip pads, cardiopathies and renal anomalies.
Commentary: The diagnosis of this condition is clinical. The characteristics in the cases are compared with the patients reported in the literature. The importance of early diagnosis is to provide preventive management and an appropriate genetic counseling for the family.
... en casos con fisura palatina 13 . Alteraciones tipo duplicaciones en 8p22/8p23.1 encontradas en algunos pacientes 14,15 no han sido descritas posteriormente 8,16,17 . Recientemente, se han referido mutaciones del gen MLL2 como una de las principales causas en pacientes con el síndrome; este estudio se ha llevado a cabo mediante una técnica novedosa aplicada en clínica: el análisis del exoma 18 . ...
... y persistencia de almohadilla en los pulpejos de los dedos; la mayoría de estos están presentes en los pacientes descritos en este artículo. Por otro lado, hay anomalías en diferentes sistemas que se presentan con menor frecuencia pero que deben descartarse en todo paciente con diagnóstico clínico de síndrome de Kabuki, dentro de las cuales están: malformaciones del sistema cardiovascular y genitourinario como lo refieren varios de los casos previamente publicados 10,17,19,20 . El cariotipo de bandas G de alta resolución suele ser normal en la mayoría de los casos. ...
... El cariotipo del caso clínico 1 exhibe un aumento de la región heterocromatina 1qh+, considerado una variante normal. Por su parte, en el caso clínico 2 el cariotipo fue normal, aunque mediante esta técnica no se puede descartar la presencia de pequeños reordenamientos cromosómicos o bajos niveles de mosaicismo, como lo descrito en otros pacientes con fenotipo Kabuki 17 . En los pacientes no se han realizado estudios de hibridación genómica comparativa (CGH), ni análisis molecular del gen MLL2 recientemente implicado, siendo el paso a seguir para poder identificar la etiología y con esto contribuir con la información para establecer la posibilidad de correlación genotipo-fenotipo 18 . ...
Kabuki syndrome (OMIM: #147 920) presents as large palpebral fissures with eversion of the lateral third of the lower eyelids, depressed nasal bridge, arched eyebrows, dysplastic ears and in most cases, with mental retardation. Patients have minor and major abnormalities in different systems. Its genetic basis is heterogeneous, but recently has been associated with mutations in gen MLL2.
We present two patients with clinical features compatibles with the syndrome, mainly: large palpebral fissures with eversion of the lateral third of the lower eyelids, depressed nasal bridge, arched eyebrows, flat nose, persistent fingertip pads, cardiopathies and renal anomalies.
The diagnosis of this condition is clinical. The characteristics in the cases are compared with the patients reported in the literature. The importance of early diagnosis is to provide preventive management and an appropriate genetic counseling for the family.
... The vast majority of reported cases are sporadic. After initial and controversial data that associated this condition to chromosomal rearrangement [4,5], mutations in the MLL2 gene identified the underlying cause of Kabuki syndrome in approximately 72% of affected individuals [6,7]. The encoded MLL2 protein is a member of the Mixed Lineage Leukemia (MLL) family of histone methyl transferases (HMT). ...
Kabuki syndrome (Niikawa-Kuroki syndrome) is a rare, multiple congenital anomalies/mental retardation syndrome characterized by a peculiar face, short stature, skeletal, visceral and dermatoglyphic abnormalities, cardiac anomalies, and immunological defects. Recently mutations in the histone methyl transferase MLL2 gene have been identified as its underlying cause.
Genomic DNAs were extracted from 62 index patients clinically diagnosed as affected by Kabuki syndrome. Sanger sequencing was performed to analyze the whole coding region of the MLL2 gene including intron-exon junctions. The putative causal and possible functional effect of each nucleotide variant identified was estimated by in silico prediction tools.
We identified 45 patients with MLL2 nucleotide variants. 38 out of the 42 variants were never described before. Consistently with previous reports, the majority are nonsense or frameshift mutations predicted to generate a truncated polypeptide. We also identified 3 indel, 7 missense and 3 splice site.
This study emphasizes the relevance of mutational screening of the MLL2 gene among patients diagnosed with Kabuki syndrome. The identification of a large spectrum of MLL2 mutations possibly offers the opportunity to improve the actual knowledge on the clinical basis of this multiple congenital anomalies/mental retardation syndrome, design functional studies to understand the molecular mechanisms underlying this disease, establish genotype-phenotype correlations and improve clinical management.
... The vast majority of reported cases are sporadic. After initial and controversial data that associated this condition to chromosomal rearrangement [4,5], mutations in the MLL2 gene identified the underlying cause of Kabuki syndrome in approximately 72% of affected individuals [6,7]. The encoded MLL2 protein is a member of the Mixed Lineage Leukemia (MLL) family of histone methyl transferases (HMT). ...
BACKGROUND: Kabuki syndrome (Niikawa-Kuroki syndrome) is a rare, multiple congenital anomalies/mental retardation syndrome characterized by a peculiar face, short stature, skeletal, visceral and dermatoglyphic abnormalities, cardiac anomalies, and immunological defects. Recently mutations in the histone methyl transferase MLL2 gene have been identified as its underlying cause. METHODS: Genomic DNAs were extracted from 62 index patients clinically diagnosed as affected by Kabuki syndrome. Sanger sequencing was performed to analyze the whole coding region of the MLL2 gene including intron-exon junctions. The putative causal and possible functional effect of each nucleotide variant identified was estimated by in silico prediction tools. RESULTS: We identified 45 patients with MLL2 nucleotide variants. 38 out of the 42 variants were never described before. Consistently with previous reports, the majority are nonsense or frameshift mutations predicted to generate a truncated polypeptide. We also identified 3 indel, 7 missense and 3 splice site. CONCLUSIONS: This study emphasizes the relevance of mutational screening of the MLL2 gene among patients diagnosed with Kabuki syndrome. The identification of a large spectrum of MLL2 mutations possibly offers the opportunity to improve the actual knowledge on the clinical basis of this multiple congenital anomalies/mental retardation syndrome, design functional studies to understand the molecular mechanisms underlying this disease, establish genotype-phenotype correlations and improve clinical management.
