Early-onset obesity and paternal 2pter deletion encompassing the ACP1, TMEM18, and MYT1L genes.

Obesity is a common but highly, clinically, and genetically heterogeneous disease. Deletion of the terminal region of the short arm of chromosome 2 is rare and has been reported in about 13 patients in the literature often associated with a Prader-Willi-like phenotype. We report on five unrelated patients with 2p25 deletion of paternal origin presenting with early-onset obesity, hyperphagia, intellectual deficiency, and behavioural difficulties. Among these patients, three had de novo pure 2pter deletions, one presented with a paternal derivative der(2)t(2;15)(p25.3;q26) with deletion in the 2pter region and the last patient presented with an interstitial 2p25 deletion. The size of the deletions was characterized by SNP array or array-CGH and was confirmed by fluorescence in situ hybridization (FISH) studies. Four patients shared a 2p25.3 deletion with a minimal critical region estimated at 1.97 Mb and encompassing seven genes, namely SH3HYL1, ACP1, TMEMI8, SNTG2, TPO, PXDN, and MYT1L genes. The fifth patient had a smaller interstitial deletion encompassing the TPO, PXDN, and MYT1L genes. Paternal origin of the deletion was determined by genotyping using microsatellite markers. Analysis of the genes encompassed in the deleted region led us to speculate that the ACP1, TMEM18, and/or MYT1L genes might be involved in early-onset obesity. In addition, intellectual deficiency and behavioural troubles can be explained by the heterozygous loss of the SNTG2 and MYT1L genes. Finally, we discuss the parent-of-origin of the deletion.

Pre- and postnatal phenotype of 6p25 deletions involving the FOXC1 gene.

FOXC1 deletion, duplication, and mutations are associated with Axenfeld-Rieger anomaly, and Dandy-Walker malformation spectrum. We describe the clinical history, physical findings, and available brain imaging studies in three fetuses, two children, and one adult with 6p25 deletions encompassing FOXC1. Various combinations of ocular and cerebellar malformations were found. In all three fetuses, necropsy including detailed microscopic assessments of the eyes and brains showed ocular anterior segment dysgenesis suggestive of Axenfeld-Rieger anomaly. Five 6p25 deletions were terminal, including two derived from inherited reciprocal translocations; the remaining 6p25 deletion was interstitial. The size and breakpoints of these deletions were characterized using comparative genomic hybridization arrays. All six deletions included FOXC1. Our data confirm that FOXC1 haploinsufficiency plays a major role in the phenotype of patients with 6p25 deletions. Histopathological features of Axenfeld-Rieger anomaly were clearly identifiable before the beginning of the third-trimester of gestation.

Prenatal diagnosis of a 7p15-p21 deletion encompassing the TWIST1 gene involved in Saethre-Chotzen syndrome.

Saethre-Chotzen syndrome is a craniosynostosis syndrome that is rarely diagnosed prenatally. It is caused by cytogenetic deletions or mutations of the TWIST1 gene. We report here a de novo prenatal case with clinically and molecularly well defined Saethre-Chotzen syndrome due to a TWIST1 deletion. This is the first reported case of a deletion encompassing the TWIST1 gene to be diagnosed prenatally. We recommend screening for a deletion of the TWIST1 gene if signs of coronal craniosynostosis with no clear etiology are observed on ultrasound examination.

Tetrasomy 13q31.1qter due to an inverted duplicated neocentric marker chromosome in a fetus with multiple malformations.

Small supernumerary marker chromosome (sSMC) lacking alpha satellite DNA or endogenous centromere regions are rare and contain fully functional centromeres, called neocentromeres. We report on a woman with a 14-week gestation pregnancy with a cystic hygroma and cerebellar hypoplasia at ultrasound examination. Cytogenetic studies showed a karyotype 47,XY,+mar dn. This sSMC was observed in chorionic villi, lung, and muscle tissue. Array Comparative Genomic Hybridization showed a gain from 13q31.1 to 13qter region. Fluorescent in situ hybridization with pan alpha satellite probe and probes specific for chromosome 13 showed a marker corresponding to an inversion duplication of the 13q distal chromosomal region without alpha satellite DNA sequence, suggesting the presence of a neocentromere. Examination of the fetus showed dysmorphic features, cystic cervical hygroma, postaxial polydactyly of the right hand and left foot with short fingers, malrotation of the gut, and a micropenis with hypospadias. Genotype-phenotype correlation in tetrasomy 13q is discussed according to the four 13q chromosomal breakpoints reported (13q32, 13q31, 13q21, 13q14) for chromosome 13 supernumerary markers.

Further delineation of the 17p13.3 microdeletion involving YWHAE but distal to PAFAH1B1: four additional patients.

BACKGROUND: The 17p13.3 deletion syndrome (or Miller-Dieker syndrome, MDS, MIM 247200) is characterized by lissencephaly, mental retardation and facial dysmorphism. The phenotype is attributed to haploinsufficiency of two genes present in the minimal critical region of MDS: PAFAH1B1 (formerly referred to as LIS1) and YWHAE. Whereas isolated PAFAH1B1 deletion causes lissencephaly, YWHAE is a candidate for the dysmorphic phenotype associated with MDS. OBJECTIVE: We describe clinical, neuroradiological and molecular data in four patients with a 17p13.3 deletion distal to PAFAH1B1 involving YWHAE. RESULTS: All patients presented with mild or moderate developmental delay and pre and/or post-natal growth retardation. Patients A, B and C had neuro-imaging anomalies: leucoencephalopathy with macrocephaly (patients A and C), Chiari type 1 malformation (patient A) and paraventricular cysts (patient C). Patient B had patent ductus arteriosus and pulmonary arterial hypertension. Patient C had unilateral club foot. Patient D had enlarged Virchow Robin spaces, microcornea, and chorioretinal and lens coloboma. Array-CGH revealed de novo terminal 17p13.3 deletions for patient A and B, and showed interstitial 17p13.3 deletions of 1.4 Mb for patient C and of 0.5 Mb for patient D. In all patients, PAFAH1B1 was not deleted. CONCLUSION: Our patients confirm that 17p deletion distal to PAFAH1B1 have a distinctive phenotype : mild mental retardation, moderate to severe growth restriction, white matter abnormalities and developmental defects including Chiari type 1 malformation and coloboma. Our patients contribute to the delineation and clinical characterization of 17p13.3 deletion distal to PAFAH1B1 and highlight the role of the region containing YWHAE in brain and eye development and in somatic growth.

Ectodermal dysplasia-like syndrome with mental retardation due to contiguous gene deletion: further clinical and molecular delineation of del(2q32) syndrome.

We report on a patient with an interstitial deletion of the long arm of chromosome 2 at 2q31.2q33.2. She had prenatal and postnatal growth retardation, microcephaly, facial dysmorphism, cleft palate, camptodactyly, bilateral talipes equinovarus, severe intellectual disability, and ectodermal anomalies. She showed thin, atrophic skin, sparse, brittle, slowly growing hair, oligodontia with abnormally shaped teeth, normal sweating, and normal fingernails, consistent with a diagnosis of ectodermal dysplasia. Array CGH analysis (Agilent 44K) showed the deletion to span 26 Mb, between cytogenetic bands 2q31.2 and 2q33. The deletion leads to hemizygosity for the HOXD cluster and its regulatory elements, COL3A1/COL5A2, GTF3C3, CASP8, CASP10, and SABT2 could perhaps interfere with long range control of DLX1 and DLX2 expression. This girl confirms the existence of a clinically recognizable 2q32 microdeletion syndrome, as recently delineated by Van Buggenhout et al. and confirms a novel putative locus for ectodermal dysplasia on chromosome 2q31q33. We recommend considering cytogenetic and/or molecular screening for del(2q32) in patients with developmental disability and ectodermal dysplasia-like phenotype, including thin skin, oligodontia, dysplastic teeth, and sparse hair.

Giant diencephalic harmartoma and related anomalies: a newly recognized entity distinct from the Pallister-Hall syndrome.

An hypothalamic hamartoma is an abnormal mass of mature glio-neuronal tissue present in the hypothalamic area. It usually measures <2 cm of diameter. Most of the time, this hamartoma occurs in Pallister-Hall syndrome (PHS), due to heterozygous GLI3 mutations. We report on five fetuses with giant diencephalic hamartoma and other midline brain and facial malformations, without mutation in the GLI3 gene or genomic rearrangements in three of them. The fetuses showed facial asymmetry, unilateral ear and eye anomalies, and facial cleft. Extracephalic malformations consisted of vertebral anomalies and short nails, without polydactyly and cardiac malformation. The diencephalon was replaced by an encephaloid mass protruding into the facial cleft. Normal cerebral structures were not detectable. In one patient, holoprosencephaly of the syntelencephalic type was noted. Arhinencephaly was present in all patients. Histologically, the ill-defined, multilobulated lesion was made of neuroblastic and neurocytic cell foci, lying in a fibrillar network, elaborating sometimes perivascular pseudorosettes, with a maturation gradient in accordance with the fetal age. Owing to their location, the tumors could be described as diencephalic, rather than hypothalamic hamartomas. The striking asymmetry of the facial anomalies and the diencephalic malformations are not in the spectrum observed with PHS and related syndromes, suggesting a distinct entity involving abnormal morphogenetic developmental fields at around 5 weeks of gestation.

Early and rapid prenatal diagnosis of monosomy 2q36.1 in trophoblast cells.

OBJECTIVES: CVS is the earliest procedure for cytogenetic analysis but the quality of metaphases obtained does not allow the characterization of subtle chromosomal anomalies. We report the application interphase fluorescence in situ hybridization for the rapid prenatal diagnosis of a subtle structural chromosome anomaly in trophoblast cells. METHODS AND RESULTS: The foetus was karyotyped because of a paternal complex chromosomal anomaly 46,XY,inv(2)(q14.3q35),ins(10;2)(q25;q36.1q36.1). Fluorescence in situ hybridization analyses were performed on interphase nuclei and metaphase chromosomes from uncultured chorionic villi using bacterial artificial chromosomes specific for the 2q chromosomal region. Direct conventional cytogenetics showed an apparently normal male karyotype, whereas fluorescence in situ hybridization analysis showed a deletion of the chromosomal region 2q36.1 and a paracentric inversion of the chromosome 2q leading to a partial monosomy 2q36.1. CONCLUSION: This strategy allowed us to offer an early and rapid chromosomal analysis for this couple leading to a better management of the pregnancy. This report demonstrates that interphase fluorescence in situ hybridization can be used in direct CVS for a rapid and early prenatal diagnosis of complex chromosomal rearrangements.

A locus for sacral/anorectal malformations maps to 6q25.3 in a 0.3 Mb interval region.

Partial absence of the sacrum is a rare congenital defect that also occurs as an autosomal-dominant trait, whereas imperforate/ectopic anus is a relatively common malformation, usually observed in multiple congenital anomalies syndromes. We report on a girl born to healthy consanguineous parents (first cousins once removed) with anal imperforation and associated rectovaginal fistula and partial sacral agenesis. Facial dysmorphism included a high forehead, epicanthic folds, downslanting palpebral fissures, hypertelorism and a depressed nasal root. Brain MRI showed a bilateral opercular dysplasia with a unilateral (right) pachygyria; MRI and X-ray imaging of the spine disclosed a tethered cord associated with partial sacral agenesis. She showed a moderate developmental delay. Ophthalmologic examination evidenced bilateral microphthalmos and relative microcornea. Cytogenetic studies in our patient disclosed a pure de novo 6q25.3 --> qter deletion. By genotype analysis, we detected in our patient a maternal allele loss encompassing D6S363 and D6S446. Pure distal 6q deletion is a rare anomaly, reported in association with sacral/anorectal malformations (sacral agenesis, anal imperforation/ectopia) and never with cortical dysplasia. Pooling deletion mapping information in patients with pure terminal and interstitial 6q deletion allowed us to define a critical region spanning 0.3 Mb between the markers D6S959 and D6S437 for sacral/anal malformations. We hypothesize that haploinsufficiency for a gene within the deleted region may impair normal development of caudal structures, possibly acting on the notochordal development. European Journal of Human Genetics (2006) 14, 971-974. doi:10.1038/sj.ejhg.5201635; published online 17 May 2006.

Discordant prenatal diagnosis of trisomy 21 due to mosaic structural rearrangements of chromosome 21.

OBJECTIVES: Trisomy 21 mosaicism associated with a structural rearrangement of chromosome 21 is uncommon. We report on two prenatal diagnoses in which karyotypes showed mosaicism with an aberrant cell line, including a structural rearrangement of chromosome 21. METHODS: Both these cases were associated with increased nuchal translucency. Conventional and molecular cytogenetic analyses were performed on uncultured and cultured trophoblast and amniotic fluid cells. RESULTS: In Case 1, analysis of trophoblast cells revealed an abnormal karyotype of 47,XX,+mar.ish der(13/21)(D13Z1/D21Z1+)/46,XX. The amniocentesis showed a free non-mosaic trisomy 21. In Case 2, the trophoblast direct analysis showed a normal male karyotype whereas the long-term culture revealed a mosaicism for a dicentric long-arm isochromosome 21: 46,XY,idic(21)(p11)/45,XY,-21/46,XY. Amniocentesis showed an unbalanced non-mosaic karyotype 46,XY,idic(21)(p11) resulting therefore in trisomy for the long arm of chromosome 21. CONCLUSION: Our cases underline the importance of combining the direct analysis and long-term culture of trophoblast and emphasise the need for confirmatory studies in other tissues when mosaicism of structural rearrangement is encountered in chorionic villi. The meiotic and mitotic mechanisms of formation of these structural rearrangements of chromosome 21 are discussed.

Isodicentric/pseudoisodicentric chromosome 21 amplification in four cases of acute myelocytic leukemia or myelodysplasia.

The bone marrow karyotypes of three patients with acute myelocytic leukemia (AML) or myelodysplastic syndrome (MDS) were studied at diagnosis and revealed, multiple copies of the same chromosomal anomaly, considered as psu idic(21)(q22) associated with other rearrangement(s). The karyotype of a fourth patient with MDS in transformation showed one copy of a dicentric marker presumably derived from a similar psu idic(21) by (tandem?) interstitial amplification of part of its structure, resembling a "homogeneous staining region", and described as der(21)psu idic(21)(q22)hsr(21)(q22). This rearrangement, previously described in isolated cases only, might be considered as recurrent in AML/MDS and associated with an unfavorable prognosis. It is most probably a secondary change, because it was never observed as sole abnormality and the main association, as for trisomy 21, was with del(5q). In the four cases, the number of partial supernumerary segmental 21pter-->21q22 copies, ranged from 2 to 10. The AML1 gene did not appear to be the common target of this amplification because this locus had been lost by the psu idic(21) in one patient