Overgrowth syndromes (OGS) comprise a heterogeneous group of disorders whose main characteristic is that the weight, height or the head circumference are above the 97th centile or 2-3 standard deviations above the mean for age, gender, and ethnic group. Several copy-number variants (CNVs) have been associated with the development of OGS, such as the 5q35 microdeletion or the duplication of the 15q26.1-qter, among many others. In this study, we have applied 850K SNP-arrays to 112 patients and relatives with OGS from the Spanish OverGrowth Registry Initiative. We have identified CNVs associated with the disorder in nine individuals (8%). Subsequently, whole genome sequencing (WGS) analysis was performed in these nine samples in order to better understand these genomic imbalances. All the CNVs were detected by both techniques, settling that WGS is a useful tool for CNV detection. We have found six patients with genomic abnormalities associated with previously well-established disorders and three patients with CNVs of unknown significance, which may be related to OGS, based on scientific literature. In this report, we describe these findings and comment on genes associated with OGS that are located within the CNV regions.

SETD2 belongs to the family of histone methyltransferase proteins and has been associated with three nosologically distinct entities with different clinical and molecular features: Luscan-Lumish syndrome (LLS), intellectual developmental disorder, autosomal dominant 70 (MRD70), and Rabin-Pappas syndrome (RAPAS). LLS [MIM #616831] is an overgrowth disorder with multisystem involvement including intellectual disability, speech delay, autism spectrum disorder (ASD), macrocephaly, tall stature, and motor delay. RAPAS [MIM #6201551] is a recently reported multisystemic disorder characterized by severely impaired global and intellectual development, hypotonia, feeding difficulties with failure to thrive, microcephaly, and dysmorphic facial features. Other neurologic findings may include seizures, hearing loss, ophthalmologic defects, and brain imaging abnormalities. There is variable involvement of other organ systems, including skeletal, genitourinary, cardiac, and potentially endocrine. Three patients who carried the missense variant p.Arg1740Gln in SETD2 were reported with a moderately impaired intellectual disability, speech difficulties, and behavioral abnormalities. More variable findings included hypotonia and dysmorphic features. Due to the differences with the two previous phenotypes, this association was then named intellectual developmental disorder, autosomal dominant 70 [MIM 620157]. These three disorders seem to be allelic and are caused either by loss-of-function, gain-of-function, or missense variants in the SETD2 gene. Here we describe 18 new patients with variants in SETD2, most of them with the LLS phenotype, and reviewed 33 additional patients with variants in SETD2 that have been previously reported in the scientific literature. This article offers an expansion of the number of reported individuals with LLS and highlights the clinical features and the similarities and differences among the three phenotypes associated with SETD2.

PURPOSE:Germline loss-of-function variants in CTNNB1 cause neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV; OMIM 615075) and are the most frequent, recurrent monogenic cause of cerebral palsy (CP). We investigated the range of clinical phenotypes owing to disruptions of CTNNB1 to determine the association between NEDSDV and CP.METHODS:Genetic information from 404 individuals with collectively 392 pathogenic CTNNB1 variants were ascertained for the study. From these, detailed phenotypes for 52 previously unpublished individuals were collected and combined with 68 previously published individuals with comparable clinical information. The functional effects of selected CTNNB1 missense variants were assessed using TOPFlash assay.RESULTS:The phenotypes associated with pathogenic CTNNB1 variants were similar. A diagnosis of CP was not significantly associated with any set of traits that defined a specific phenotypic subgroup, indicating that CP is not additional to NEDSDV. Two CTNNB1 missense variants were dominant negative regulators of WNT signaling, highlighting the utility of the TOPFlash assay to functionally assess variants.CONCLUSION:NEDSDV is a clinically homogeneous disorder irrespective of initial clinical diagnoses, including CP, or entry points for genetic testing.

The congenital disorders of glycosylation (CDG) are defects in glycoprotein and glycolipid glycan synthesis and attachment. They affect multiple organ/systems, but non-specific symptoms render the diagnosis of the different CDG very challenging. Phosphomannomutase 2 (PMM2)-CDG is the most common CDG, but advances in genetic analysis have shown others to occur more commonly than previously thought. The present work reports the clinical and mutational spectrum of 25 non-PMM2 CDG patients. The most common clinical symptoms were hypotonia (80%), motor or psychomotor disability (80%) and craniofacial dysmorphism (76%). Based on their serum transferrin isoform profile, 18 were classified as CDG-I and 7 as CDG-II. Pathogenic variations were found in 16 genes (ALG1, ALG6, ATP6V0A2, B4GALT1, CCDC115, COG7, DOLK, DPAGT1, DPM1, GFPT1, MPI, PGM1, RFT1, SLC35A2, SRD5A3, and SSR4). Overall, 27 variants were identified, 12 of which are novel. The results highlight the importance of combining genetic and biochemical analyses for the early diagnosis of this heterogeneous group of disorders.

A human induced pluripotent stem cell (iPSC) line was generated from fibroblasts of a patient with nonketotic hyperglycinemia bearing the biallelic changes c.1742C > G (p.Pro581Arg) and c.2368C > T (p.Arg790Trp) in the GLDC gene. Reprogramming factors OCT3/4, SOX2, KLF4 and c-MYC were delivered using a non-integrative method based on the Sendai virus. Once established, iPSCs have shown full pluripotency, differentiation capacity and genetic stability. This cellular model provides a good resource for disease modeling and drug discovery.

There is an increasing implication of non-coding regions in pathological processes of genetic origin. This is partly due to the emergence of sophisticated techniques that have transformed research into gene expression by allowing a more global understanding of the genome, both at the genomic, epigenomic and chromatin levels. Here, we implemented the analysis of PAX6, whose coding loss-of-function variants are mainly implied in aniridia, by studying its non-coding regions (untranslated regions, introns and cis-regulatory sequences). In particular, we have taken advantage of the development of high-throughput approaches to screen the upstream and downstream regulatory regions of PAX6 in 47 aniridia patients without identified mutation in the coding sequence. This was made possible through the use of custom targeted resequencing and/or CGH array to analyze the entire PAX6 locus on 11p13. We found candidate variants in 30 of the 47 patients. 9/30 correspond to the well-known described 3′ deletions encompassing SIMO and other enhancer elements. In addition, we identified numerous different variants in various non-coding regions, in particular untranslated regions. Among these latter, most of them demonstrated an in vitro functional effect using a minigene strategy, and 12/21 are thus considered as causative mutations or very likely to explain the phenotypes. This new analysis strategy brings molecular diagnosis to more than 90% of our aniridia patients. This study revealed an outstanding mutation pattern in non-coding PAX6 regions confirming that PAX6 remains the major gene for aniridia.

The aim of this study was to identify the causative genetic lesion in two apparently unrelated newborns having lethal lactic acidosis, multi-organ failure and congenital malformations including interrupted aortic arch, who exhibited mild methylmalonic aciduria, combined mitochondrial respiratory chain deficiency, and marked muscle mitochondrial DNA depletion. A novel mutation in the SUCLG1 gene was identified. Phenotype severity in Succinate-CoA ligase dysfunction appears to be more correlated to the muscle mtDNA content than to the tissue distribution of the heterodimer subunits. Prominent impairment of mitochondrial respiratory chain may result in deep ravages in developmental tissues leading to multiple organ failure and malformations.

Clinical GeneticsVolume 72, Issue 4 p. 384-386 Germinal mosaicism in Simpson-Golabi-Behmel syndrome V Romanelli, V Romanelli Department of Medical and Molecular Genetics, Pathology and Paediatric Endocrinology, Hospital Universitario La Paz, Madrid, SpainSearch for more papers by this authorI Arroyo, I Arroyo Department of Paediatrics and Neonatology, Hospital San Pedro de Alcántara, Cáceres, SpainSearch for more papers by this authorJI Rodriguez, JI Rodriguez Department of Medical and Molecular Genetics, Pathology and Paediatric Endocrinology, Hospital Universitario La Paz, Madrid, SpainSearch for more papers by this authorL Magano, L Magano Department of Medical and Molecular Genetics, Pathology and Paediatric Endocrinology, Hospital Universitario La Paz, Madrid, SpainSearch for more papers by this authorP Arias, P Arias Department of Medical and Molecular Genetics, Pathology and Paediatric Endocrinology, Hospital Universitario La Paz, Madrid, SpainSearch for more papers by this authorI Incera, I Incera Department of Medical and Molecular Genetics, Pathology and Paediatric Endocrinology, Hospital Universitario La Paz, Madrid, SpainSearch for more papers by this authorR Gracia-Bouthelier, R Gracia-Bouthelier Department of Medical and Molecular Genetics, Pathology and Paediatric Endocrinology, Hospital Universitario La Paz, Madrid, SpainSearch for more papers by this authorP Lapunzina, Corresponding Author P Lapunzina Department of Medical and Molecular Genetics, Pathology and Paediatric Endocrinology, Hospital Universitario La Paz, Madrid, SpainDr Pablo LapunzinaDepartment of Medical and Molecular GeneticsHospital Universitario La PazAutónoma University of MadridPaseo de la Castellana 26128046 MadridSpainTel.: +34 91 727 72 17Fax: +34 91 207 10 40e-mail: [email protected]Search for more papers by this author V Romanelli, V Romanelli Department of Medical and Molecular Genetics, Pathology and Paediatric Endocrinology, Hospital Universitario La Paz, Madrid, SpainSearch for more papers by this authorI Arroyo, I Arroyo Department of Paediatrics and Neonatology, Hospital San Pedro de Alcántara, Cáceres, SpainSearch for more papers by this authorJI Rodriguez, JI Rodriguez Department of Medical and Molecular Genetics, Pathology and Paediatric Endocrinology, Hospital Universitario La Paz, Madrid, SpainSearch for more papers by this authorL Magano, L Magano Department of Medical and Molecular Genetics, Pathology and Paediatric Endocrinology, Hospital Universitario La Paz, Madrid, SpainSearch for more papers by this authorP Arias, P Arias Department of Medical and Molecular Genetics, Pathology and Paediatric Endocrinology, Hospital Universitario La Paz, Madrid, SpainSearch for more papers by this authorI Incera, I Incera Department of Medical and Molecular Genetics, Pathology and Paediatric Endocrinology, Hospital Universitario La Paz, Madrid, SpainSearch for more papers by this authorR Gracia-Bouthelier, R Gracia-Bouthelier Department of Medical and Molecular Genetics, Pathology and Paediatric Endocrinology, Hospital Universitario La Paz, Madrid, SpainSearch for more papers by this authorP Lapunzina, Corresponding Author P Lapunzina Department of Medical and Molecular Genetics, Pathology and Paediatric Endocrinology, Hospital Universitario La Paz, Madrid, SpainDr Pablo LapunzinaDepartment of Medical and Molecular GeneticsHospital Universitario La PazAutónoma University of MadridPaseo de la Castellana 26128046 MadridSpainTel.: +34 91 727 72 17Fax: +34 91 207 10 40e-mail: [email protected]Search for more papers by this author First published: 29 August 2007 https://doi.org/10.1111/j.1399-0004.2007.00871.xCitations: 13Read 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 References 1 Hughes-Benzie RM, Hunter AG, Allanson JE, Mackenzie AE. Simpson-Golabi-Behmel syndrome associated with renal dysplasia and embryonal tumors: localization of the gene to Xqcen-q21. Am J Med Genet 1992: 43: 428– 435. 2 Weidle B, Orstavik KH. Simpson-Golabi-Behmel syndrome. A new overgrowth syndrome with increased risk of tumor development. Tidsskr Nor Laegeforen 1998: 118: 1556– 1558. 3 Behmel A, Plochl E, Rosenkranz W. A new X-linked dysplasia gigantism síndrome: identical with the Simpson dysplasia síndrome? Hum Genet 1984: 67: 409– 413. 4 Golabi M, Rosen L. A new X-linked mental retardation-overgrowth syndrome. Am J Med Genet 1984: 17: 345– 358. 5 Neri G, Marini R, Cappa M, Borrelli P, Opitz JM. Simpson-Golabi-Behmel syndrome: an X-linked encephalo-tropho-schisis syndrome. Am J Med Genet 1988: 30: 287– 299. 6 Lapunzina P, Badia I, Galoppo C, De Matteo E et al. A patient with Simpson-Golabi-Behmel syndrome and hepatocellular carcinoma. 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