Recently, pathogenic variants in the MLL2 gene were identified as the most common cause of Kabuki (Niikawa-Kuroki) syndrome (MIM#147920). To further elucidate the genotype-phenotype correlation, we studied a large cohort of 86 clinically defined patients with Kabuki syndrome (KS) for mutations in MLL2. All patients were assessed using a standardized phenotype list and all were scored using a newly developed clinical score list for KS (MLL2-Kabuki score 0-10). Sequencing of the full coding region and intron-exon boundaries of MLL2 identified a total of 45 likely pathogenic mutations (52%): 31 nonsense, 10 missense and four splice-site mutations, 34 of which were novel. In five additional patients, novel, i.e. non-dbSNP132 variants of clinically unknown relevance, were identified. Patients with likely pathogenic nonsense or missense MLL2 mutations were usually more severely affected (median 'MLL2-Kabuki score' of 6) as compared to the patients without MLL2 mutations (median 'MLL2-Kabuki score' of 5), a significant difference (p < 0.0014). Several typical facial features such as large dysplastic ears, arched eyebrows with sparse lateral third, blue sclerae, a flat nasal tip with a broad nasal root, and a thin upper and a full lower lip were observed more often in mutation positive patients.

Summary Background Conradi–Hünermann–Happle syndrome (CDPX2, OMIM 302960) is an inherited X-linked dominant variant of chondrodysplasia punctata which primarily affects the skin, bones and eyes. CDPX2 results from mutations in EBP (emopamil binding protein), and presents with increased levels of sterol precursors 8(9)-cholestenol and 8-dehydrocholesterol. Objectives To expand the understanding of CDPX2, clinically, biochemically and genetically. Methods We present one of the largest series reported to date, including 13 female patients belonging to nine Spanish families. Patients were studied biochemically using gas chromatography–mass spectrometry, genetically using polymerase chain reaction and in their methylation status using the HUMARA assay. Results In our cases, there was a clear relationship between abnormal sterol profile and the EBP gene mutation. We describe three novel mutations in the EBP gene. EBP mutations were inherited in three out of nine families and were sporadic in the remaining cases. Conclusions No clear genotype–phenotype correlation was found. Patients’ biochemical profiles did not reveal a relationship between sterol profiles and severity of disease. A skewed X-chromosome inactivation may explain the clinical phenotype in CDPX2 in some familial cases.

The 22q11.2 deletion is a common chromosomal deletion syndrome, with a postnatal prevalence of 1 : 4000 newborns, with dominant autosomical inherited and with a wide phenotypical and clinical variability, which includes Velo-Cardio-Facial syndrome (VCFS/del 22q11), DiGeorge syndrome, Shprintzen, Takao (conotruncal anomaly face syndrome) and Cayler syndrome. The diagnose of this disease is important because it is a multisystemic disease that has different clinical expressions: congenital heart disease (conotruncal defect the most frequent), immunological abnormalities (cellular immunity) endocrynological abnormalities, palate/facial defects, dysmorphies, skeletal and neurological abnormalities. The prenatal prevalence it is probably more elevated than the postnatal prevalence, with a described prevalence of 1.6–11.5% in some series. The aim of our study is to present our experience in prenatal diagnose, using the in situ hybridization (FISH technique) of fetuses with congenital heart disease (CHD). We studied 110 fetuses with a CHD using FISH technique (Tuple I probe, 22q13 marker, Vysis), by the analysis of cultivated corial velocities (3 cases), cultivated amniotic fluid (61 cases), non-cultivated amniotic fluid (37 cases) and fetal blood (9 cases). We detect the critical deletion zone of DiGeorge and velocardiofacial syndrome in 4 fetuses (it represents a prevalence of 4%), which all of them were de novo mutations. In situ hybridization (FISH technique), is a pretty good method for the diagnose of 22q11.2 deletion in different fetal tissues. As in other series, our prenatal prevalence is much more elevated than the postnatal prevalence.

BACKGROUNDAndrogen receptor (AR) gene mutations are the most frequent cause of 46,XY disorders of sex development (DSD) and are associated with a variety of phenotypes, ranging from phenotypic women [complete androgen insensitivity syndrome (CAIS)] to milder degrees of undervirilization (partial form or PAIS) or men with only infertility (mild form or MAIS).OBJECTIVEThe aim of the study was to characterize the contribution of the AR gene to the molecular cause of 46,XY DSD in a series of Spanish patients.SETTINGWe studied a series of 133 index patients with 46,XY DSD in whom gonads were differentiated as testes, with phenotypes including varying degrees of undervirilization, and in whom the AR gene was the first candidate for a molecular analysis.METHODSThe AR gene was sequenced (exons 1 to 8 with intronic flanking regions) in all patients and in family members of 61% of AR-mutated gene patients.RESULTSAR gene mutations were found in 59 individuals (44.4% of index patients), of whom 46 (78%) were CAIS and 13 (22%) PAIS. Fifty-seven different mutations were found: 21.0% located in exon 1, 15.8% in exons 2 and 3, 57.9% in exons 4-8, and 5.3% intronic. Twenty-three mutations (40.4%) had been previously described and 34 (59.6%) were novel.CONCLUSIONSAR gene mutation is the most frequent cause of 46,XY DSD, with a clearly higher frequency in the complete phenotype. Mutations spread along the whole coding sequence, including exon 1. This series shows that 60% of mutations detected during the period 2002-2009 were novel.

Tetrasomy of short arm of chromosome 9 constitutes a clinically recognizable chromosomal syndrome. Isochromosome 9p shows a strong propensity to tissue‐limited mosaicism. It occurs predominantly in peripheral blood cultures, often at a lower frequency or even absent in skin, amniotic fluid or chorionic villous cell cultures. Tissue‐limited nature of mosaicism may render prenatal detection of this condition very difficult. Herein, we report two new cases of mosaic tetrasomy 9p. Conventional cytogenetics (CC) and FISH studies demonstrated a differential expression of the mosaicism in several tissues. We review the literature and discuss the implications of these findings in cytogenetic prenatal diagnosis. © 2003 Wiley‐Liss, Inc.

American Journal of Medical Genetics Part AVolume 117A, Issue 1 p. 85-86 Research Letter Prenatal diagnosis of a rare chromosomal instability syndrome: Variegated aneuploidy related to premature centromere division (PCD) A. Plaja, Corresponding Author A. Plaja aplaja.@cs.vhebron.es Unitat de Genètica, H. Materno-Infantil Vall d'Hebron, Barcelona, SpainUnitat de Genètica, Hospital Materno-Infantil Vall d'Hebron, Pg. Vall d'Hebron 119-129, 08035 Barcelona, Spain.Search for more papers by this authorC. Mediano, C. Mediano Unitat de Genètica, H. Materno-Infantil Vall d'Hebron, Barcelona, SpainSearch for more papers by this authorL. Cano, L. Cano Unitat de Genètica, H. Materno-Infantil Vall d'Hebron, Barcelona, SpainSearch for more papers by this authorT. Vendrell, T. Vendrell Unitat de Genètica, H. Materno-Infantil Vall d'Hebron, Barcelona, SpainSearch for more papers by this authorE. Sarret, E. Sarret Unitat de Genètica, H. Materno-Infantil Vall d'Hebron, Barcelona, SpainSearch for more papers by this authorI. Farràn, I. Farràn Unitat de Diagnos̀tic Prenatal, H. Materno-Infantil Vall d'Hebron, Barcelona, SpainSearch for more papers by this authorM.A. Sánchez, M.A. Sánchez Unitat de Diagnos̀tic Prenatal, H. Materno-Infantil Vall d'Hebron, Barcelona, SpainSearch for more papers by this author A. Plaja, Corresponding Author A. Plaja aplaja.@cs.vhebron.es Unitat de Genètica, H. Materno-Infantil Vall d'Hebron, Barcelona, SpainUnitat de Genètica, Hospital Materno-Infantil Vall d'Hebron, Pg. Vall d'Hebron 119-129, 08035 Barcelona, Spain.Search for more papers by this authorC. Mediano, C. Mediano Unitat de Genètica, H. Materno-Infantil Vall d'Hebron, Barcelona, SpainSearch for more papers by this authorL. Cano, L. Cano Unitat de Genètica, H. Materno-Infantil Vall d'Hebron, Barcelona, SpainSearch for more papers by this authorT. Vendrell, T. Vendrell Unitat de Genètica, H. Materno-Infantil Vall d'Hebron, Barcelona, SpainSearch for more papers by this authorE. Sarret, E. Sarret Unitat de Genètica, H. Materno-Infantil Vall d'Hebron, Barcelona, SpainSearch for more papers by this authorI. Farràn, I. Farràn Unitat de Diagnos̀tic Prenatal, H. Materno-Infantil Vall d'Hebron, Barcelona, SpainSearch for more papers by this authorM.A. Sánchez, M.A. Sánchez Unitat de Diagnos̀tic Prenatal, H. Materno-Infantil Vall d'Hebron, Barcelona, SpainSearch for more papers by this author First published: 18 September 2002 https://doi.org/10.1002/ajmg.a.10810Citations: 10Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume117A, Issue115 February 2003Pages 85-86 RelatedInformation

Chromosome alterations, including numerical and structural chromosome rearrangements, are implicated in abnormal fetal development and congenital malformations. At least 50% of all first trimester spontaneous abortions are cytogenetically abnormal and about 6% of all postnatal congenital malformations are related to visible cytogenetic alterations detected by conventional G banding.1, 2 These percentages will probably increase with the use of molecular cytogenetic methods such as fluorescence in situ hybridisation (FISH) and comparative genomic hybridisation (CGH) in prenatal and postnatal diagnosis,3 because they will allow the detection of chromosome abnormalities that are not identified at present. The recurrent association of particular chromosome aberrations with specific clinical features has defined many chromosomal syndromes. In order to facilitate the identification of genes involved in specific human malformations, Brewer et al 4 have constructed a chromosome map of autosomal deletions (non-mosaic) associated with 47 different congenital malformations in 1753 patients. In this review, no congenital malformations were related to anomalies of 16p. So far, only the ATR-16 syndrome (α thalassaemia-retardation-16) associated with 16p13.3 deletion has been described.5–7 Interstitial deletions are relatively rare chromosomal anomalies that usually arise de novo. Here we describe multiple congenital malformations associated with a de novo interstitial chromosome deletion 16p11.2 confirmed by CGH. This is the first case reported with a phenotype-genotype correlation for this chromosome band. An ultrasound examination at 20 weeks of gestation showed the presence of cardiac defects and unilateral multiple renal cysts. Conventional cytogenetic analyses carried out …

We present three patients with variegated aneuploidy and premature centromere division (PCD), a rare chromosomal abnormality in humans. Comparison of these three and eight other patients with variegated aneuploidy related to PCD demonstrates a phenotype comprising most frequently microcephaly, CNS anomalies (with cerebellar affection and migration defects), mental retardation, pre-and postnatal growth retardation, flat and broad nasal bridge, apparently low-set ears, eye and skin abnormalities, and ambiguous genitalia in male patients. The occurrence of Wilms tumor in three patients, rhabdomyosarcoma in two others and acute leukemia in a fifth characterizes this condition as a chromosome or genome instability disorder with a high risk of malignancy. FISH studies in uncultured blood and buccal smear cells demonstrate that the random aneuploidies are not limited to cultured cells, but also occur in vivo.