Syndromic obesity is defined by the association of obesity with one or more feature(s) including developmental delay, dysmorphic traits, and/or congenital malformations. Over 25 syndromic forms of obesity have been identified. However, most cases remain of unknown etiology. The aim of this study was to identify new candidate loci associated with syndromic obesity to find new candidate genes and to better understand molecular mechanisms involved in this pathology. We performed oligonucleotide microarray‐based comparative genomic hybridization in a cohort of 100 children presenting with syndromic obesity of unknown etiology, after exhaustive clinical, biological, and molecular studies. Chromosomal copy number variations were detected in 42% of the children in our cohort, with 23% of patients with potentially pathogenic copy number variants. Our results support that chromosomal rearrangements are frequently associated with syndromic obesity with a variety of contributory genes having relevance to either obesity or developmental delay. A list of inherited or apparently de novo duplications and deletions including their enclosed genes and not previously linked to syndromic obesity was established. Proteins encoded by several of these genes are involved in lipid metabolism (ACOXL, MSMO1, MVD, and PDZK1) linked with nervous system function (BDH1 and LINGO2), neutral lipid storage (PLIN2), energy homeostasis and metabolic processes (CDH13, CNTNAP2, CPPED1, NDUFA4, PTGS2, and SOCS6). © 2014 Wiley Periodicals, Inc.

Pure distal monosomy of the long arm of chromosome 10 is a rare cytogenetic abnormality. The location and size of the deletions described in this region are variable. Nevertheless, the patients share characteristic facial appearance, variable cognitive impairment and neurobehavioral manifestations. A Minimal Critical Region corresponding to a 600 kb Smallest Region of deletion Overlap (SRO) has been proposed. In this report, we describe four patients with a distal 10q26 deletion, who displayed attention-deficit/hyperactivity disorders (ADHD). One of them had a marked behavioral profile and relatively preserved cognitive functions. Interestingly, the SRO was not included in the deleted segment of this patient suggesting that this deletion could contain candidate genes involved in the control of neurobehavioral functions. One of these candidates was the CALY gene, known for its association with ADHD patients and whose expression level was shown to be correlated with neurobehavioral disturbances in varying animal models. This report emphasizes the importance of the behavioral problems as a cardinal feature of the 10q microdeletion syndrome. Haploinsufficiency of CALY could play a crucial role in the development of the behavioral troubles within these patients.

Small supernumerary marker chromosomes (sSMCs) are structurally abnormal chromosomes that cannot be characterized by karyotype. In many prenatal cases of de novo sSMC, the outcome of pregnancy is difficult to predict because the euchromatin content is unclear. This study aimed to determine the presence or absence of euchromatin material of 39 de novo prenatally ascertained sSMC by array-comparative genomic hybridization (array-CGH) or single nucleotide polymorphism (SNP) array. Cases were prospectively ascertained from the study of 65,000 prenatal samples [0.060%; 95% confidence interval (CI), 0.042-0.082]. Array-CGH showed that 22 markers were derived from non-acrocentric markers (56.4%) and 7 from acrocentic markers (18%). The 10 additional cases remained unidentified (25.6%), but 7 of 10 could be further identified using fluorescence in situ hybridization; 69% of de novo sSMC contained euchromatin material, 95.4% of which for non-acrocentric markers. Some sSMC containing euchromatin had a normal phenotype (31% for non-acrocentric and 75% for acrocentric markers). Statistical differences between normal and abnormal phenotypes were shown for the size of the euchromatin material (more or less than 1 Mb, p = 0.0006) and number of genes (more or less than 10, p = 0.0009). This study is the largest to date and shows the utility of array-CGH or SNP array in the detection and characterization of de novo sSMC in a prenatal context.

En France, dans le cadre de l’assistance medicale a la procreation (AMP) avec tiers donneur, il est propose de lever l’anonymat de la personne qui a donne ses gametes, afin de pouvoir avoir acces a ses «origines genetiques»: tel est un des leitmotivs maintes fois proclame «haut et fort», tant le nombre d’enfants en recherche de leur «geniteur» est grandement minoritaire (de l’ordre de 25 sur 50 000 enfants nes par insemination avec donneur [IAD]). Leur porte-parole, A. Kermalvezen, n’a-t-il, d’ailleurs, pas ecrit, alors que tout le monde s’accorde a dire qu’il s’agit davantage d’une recherche du donneur en tant que personne: «Mon histoire est pour ainsi dire sans debut puisque je n’ai pas acces a mes origines genetiques» [1].

Genetics of Holoprosencephaly (HPE), a congenital malformation of the developing human forebrain, is due to multiple genetic defects. Most genes that have been implicated in HPE belong to the sonic hedgehog signaling pathway. Here we describe a new candidate gene isolated from array comparative genomic hybridization redundant 6qter deletions, DELTA Like 1 (DLL1), which is a ligand of NOTCH. We show that DLL1 is co-expressed in the developing chick forebrain with Fgf8. By treating chick embryos with a pharmacological inhibitor, we demonstrate that DLL1 interacts with FGF signaling pathway. Moreover, a mutation analysis of DLL1 in HPE patients revealed a three-nucleotide deletion. These various findings implicate DLL1 in early patterning of the forebrain and identify NOTCH as a new signaling pathway involved in HPE.

Polyvalvular heart disease has been reported in a handful of "private" syndromes that have been recently suggested to represent a single dominantly inherited condition, the polyvalvular heart disease syndrome. We report five cases in two unrelated families (one sporadic case in the first family and three siblings and their father in the second family) with the same association of polyvalvular heart disease, distinctive facial appearance, and, except the father in family 2, major joint hypermobility. Interestingly, in three of our patients (2 siblings and the sporadic case), electron microscopy revealed characteristic ultrastructural skin abnormalities with abnormal amorphous or microfibrillar deposits under the capillary basal membrane in the papillary dermis, suggestive of a connective tissue disorder, but different from Marfan syndrome or Ehlers-Danlos syndrome. Moreover, in family 2, three others sibs died in early infancy of their heart defect. Our two families and the other published cases might illustrate intrafamilial and interfamilial variability within a single condition. However, our two families disclose major joint hypermobility, normal stature, and ultrastructural skin abnormalities that were not described in the previous reports. These discrepancies let us to consider them as affected by a distinct disorder of the connective tissue.

We report the case of a patient (followed from birth to 15 years) presenting with trisomy 12 mosaicism, and focus on the endocrine phenotype associating a pituitary malformation and ovarian abnormalities. We describe the dysmorphic features and their evolution, the growth retardation and ovarian symptoms. Complete growth hormone deficiency was confirmed on auxological data, stimulation test and was related to pituitary stalk interruption, diagnosed by magnetic resonance imaging. Effect of growth hormone treatment was satisfactory resulting in a normal adult height. She also presented premature thelarche associated with right ovarian hypertrophy (4 to 5 fold the volume of the left ovary) which remained constant until 15 years of age. Diagnosis of trisomy 12 mosaicism was made on skin and ovarian karyotypes. The possible relation between these endocine findings and some genes located on chromosome 12 involved in pituitary and ovarian development is discussed.

Thirty patients have been described with cytogenetically visible deletion of the short arm of chromosome 6. However, subtelomeric 6p deletion detected by subtelomeric specific probes has been reported only twice. We report two new patients with terminal 6p deletion detected by subtelomeric screening using fluorescence in situ hybridization (FISH). The two patients exhibited mental retardation, ocular abnormalities, hearing loss, and a characteristic facial appearance. Detailed FISH analyses with probes covering the distal 6p25 region estimated the size of the terminal deletions to ≈5.5 Mb and ≈4.8 Mb. Array‐based comparative genomic hybridization (array CGH) was used to confirm the cryptic deletions. Most patients with subtelomeric defects lack a characteristic phenotype. However, some of the subtelomeric deletions result in a specific phenotype, which can direct the clinician towards the diagnosis. Submicroscopic 6p deletion appears to be a recognizable clinical phenotype, and this region should be thoroughly investigated with FISH probes, including at least a subtelomeric 6p probe and a probe covering FOXC1 , for patients presenting with a characteristic facial appearance, ocular abnormalities, predominantly anterior‐chamber eye defects, hearing loss, and mental retardation. © 2004 Wiley‐Liss, Inc.

The Albright hereditary osteodystrophy‐like (AHO‐like) syndrome was recently defined as a rare dysmorphic syndrome including brachymetaphalangism and mental retardation. This phenotype occurs in Albright hereditary osteodystrophy (AHO) but unlike it, the level of the Gs alpha protein activity is not reduced. To date 59 patients with these clinical and biochemical features have been reported, and for the majority of them (57/59) a cytogenetically visible 2q37 deletion has been observed. We report a new case of typical AHO‐like syndrome with normal karyotype. Using the polymorphic marker D2S125 we found a loss of heterozygosity suggestive of a de novo 2q37 deletion of maternal origin. This hypothesis was confirmed by FISH analysis with a subtelomeric 2q probe containing the D2S90 marker. Genotypic analysis allowed us to map the proximal breakpoint of the subtelomeric deletion within an interval delimited by D2S2338 (present) and D2S2253 (deleted). This 2q subtelomeric deletion as small as 4 Mb is to date the smallest one observed in association with a typical AHO‐like phenotype, and allows us to move the centromeric boundary of the AHO‐like critical region by 750 kb towards the 2q telomere. © 2004 Wiley‐Liss, Inc.

N This is the largest series of patients to have been molecularly characterised and includes the r( 22) patient with the smallest deletion described to date.The minimum critical region responsible for the monosomy 22q13 phenotype includes the genes PROSAP2/SHANK3, ACR, and RABL2B, but not ARSA.

The common clinical features reported in ring chromosome 22 cases include overall developmental delay with severe speech disability, growth retardation with frequently associated microcephaly, hypotonia, and dysmorphic traits, such as epicanthus, normally placed but large and dysplastic ears, long eyelashes with full eyebrows, and occasionally high arched palate, dental malocclusion, and mild hypertelorism.1–9 Second and third toe syndactyly, unsteady gait, hyperactivity, aggressive behaviour, autistic disorders,3, 4 and seizures or abnormal EEG1, 2 have also been reported. The recently described subtelomeric 22q deletion syndrome showed overlapping clinical features with a generalised developmental delay, particularly severe in the area of expressive speech.10–14 The phenotype is usually more severe in cases of ring chromosome 22 compared with subtelomeric 22q deletions. The phenotypic differences, particularly the growth retardation with microcephaly and the severe mental delay, could be the result of a larger deletion size in ring chromosome 22 cases. We report the molecular cytogenetic analysis of a ring chromosome 22 in a young boy investigated for global development and severe speech delay. This is the first molecular analysis of a ring chromosome 22 harbouring the second smallest 22qter microdeletion reported so far. Characteristics of cases with ring chromosome 22 and subtelomeric 22q deletion are reviewed. ### Case report The patient, a 7 year old boy, was seen for evaluation of global developmental delay. He was born to healthy, non-consanguineous parents aged 35 (mother) and 39 (father) years. His two older sisters were normal. Pregnancy, delivery, and the neonatal period were uneventful. His birth weight was 3330 g (50th centile), length was 50 cm (25th centile), and head circumference was …

Adenylosuccinate lyase deficiency (MIM 103050, ADSL) is a rare autosomal recessive disease causing severe mental retardation and/or autistic features.1,2 Seizures are often observed (80%),3 varying in age of onset (from newborn to late childhood) and nature (tonic-clonic, “suppression burst” pattern, West syndrome, etc), and are very often resistant to all medication. Around 50% of the children show autistic-like behaviour.4 Microcephaly is rare (1/13 of reported cases). Non-specific anomalies of the brain, such as hypoplasia of the vermis, cerebral atrophy,5 lack of myelination,6 white matter anomalies,7 and lissencephaly4 have often been described. ADSL is a homotetramer involved in two distinct steps of purine synthesis, namely (1) the conversion of succinylaminoimidazole carboxamide ribotide (SAICAR) into aminoimidazole carboxamide ribotide (AICAR), and (2) the conversion of adenylosuccinate (S-AMP) into adenosine monophosphate (AMP) in the inosine monophosphate transformation pathway (fig 1). The diagnosis of ADSL deficiency is based on the detection of dephosphorylated SAICAR and S-AMP products, that is, S-Ado (succinyladenosine) and SAICAr (succinylaminoimidazole carboxamide riboside). The modified Bratton-Marshall test is the most …