The phenotypic spectrum of duplication 5q35.2-q35.3 encompassing NSD1: is it really a reversed Sotos syndrome?

Loss-of-function mutations of NSD1 and 5q35 microdeletions encompassing NSD1 are a major cause of Sotos syndrome (Sos), which is characterized by overgrowth, macrocephaly, characteristic facies, and variable intellectual disability (ID). Microduplications of 5q35.2-q35.3 including NSD1 have been reported in only five patients so far and described clinically as a reversed Sos resulting from a hypothetical gene dosage effect of NSD1. Here, we report on nine patients from five families with interstitial duplication 5q35 including NSD1 detected by molecular karyotyping. The clinical features of all 14 individuals are reviewed. Patients with microduplications including NSD1 appear to have a consistent phenotype consisting of short stature, microcephaly, learning disability or mild to moderate ID, and distinctive facial features comprising periorbital fullness, short palpebral fissures, a long nose with broad or long nasal tip, a smooth philtrum and a thin upper lip vermilion. Behavioral problems, ocular and minor hand anomalies may be associated. Based on our findings, we discuss the possible etiology and conclude that it is possible, but so far unproven, that a gene dosage effect of NSD1 may be the major cause.

A phenotype map for 14q32.3 terminal deletions.

Detailed molecular-cytogenetic studies combined with thorough clinical characterization are needed to establish genotype-phenotype correlations for specific chromosome deletion syndromes. Although many patients with subtelomeric deletions have been reported, the phenotype maps for many of the corresponding syndromes, including the terminal deletion 14q syndrome, are only slowly emerging. Here, we report on five patients with terminal partial monosomy of 14q32.3 and characteristic features of terminal deletion 14q syndrome. Four of the patients carry de novo terminal deletions of 14q, three of which have not yet been reported. One patient carries an unbalanced translocation der(14)t(9;14)(q34.3;q32.3). Minimum deletion sizes as determined by molecular karyotyping and FISH are 5.82, 5.56, 4.17, 3.54, and 3.29 Mb, respectively. Based on our findings and a comprehensive review of the literature, we refine the phenotype map for typical clinical findings of the terminal deletion 14q syndrome (i.e., intellectual disability/developmental delay, muscular hypotonia, postnatal growth retardation, microcephaly, congenital heart defects, genitourinary malformations, ocular coloboma, and several dysmorphic signs). Combining this phenotype map with benign copy-number variation data available from the Database of Genomic Variants, we propose a small region critical for certain features of the terminal deletion 14q syndrome which contains only seven RefSeq genes.

Autosomal-dominant non-syndromic anal atresia: sequencing of candidate genes, array-based molecular karyotyping, and review of the literature.

INTRODUCTION: Anorectal malformations (ARM) range from mild anal to severe anorectal anomalies. Approximately 50% are estimated to be non-syndromic with multiple familial cases reported that suggest underlying genetic factors. These, however, still await identification. MATERIALS AND METHODS: We report a familial case of non-syndromic ARM with a mother and her two children being affected. Mother and daughter had mild ARM that had only been diagnosed after the index patient was born with a more severe form and ultrashort Hirschsprung's disease. To reveal the genetic cause in our family genome-wide array analysis was carried out to ascertain microaberrations characterized by loss or gain of genomic material. In addition, sequence analysis of four major Hirschsprung's disease genes (RET, EDNRB, EDN3, and GDNF) and the HLXB9 gene was performed to identify a mutation common to all three family members; however, these analyses did not reveal any causal genetic alteration. To demonstrate the frequency of familial non-syndromic cases, we performed a literature search revealing 59 families with at least two affected members. Sufficient description of ARM phenotype and affection status of relatives to surely classify them as familial non-syndromic forms was given for 22 families. CONCLUSION: The present family suggests that mild ARM may be overlooked in patients with non-specific clinical symptoms and that the incidence of ARM may thus be higher than previously estimated. With the new possibilities of whole exome sequencing, even small families hold the possibility to identify causal defects.

Rare interstitial deletion 9q31.2 to q33.1 de novo: longitudinal study in a patient over a period of more than 20 years.

The female carrier of a de novo interstitial deletion 9q [karyotype 46,XX,del(9)(q31.2q33.1)] was followed up over a period of more than 20 years. She shows facial dysmorphisms and significant growth retardation. Motor abilities are restricted by muscular hypotonia and malposition of the feet. She has mental retardation. There was no speech development and phases of autism were reported. By analyses with FISH and short tandem repeat markers, the interstitial deletion was confirmed and characterized to span 9q31.2q33.1, comprising at least 7.07 Mb. The aberration is of paternal origin.

Expansion of the genotypic and phenotypic spectrum in patients with KRAS germline mutations.

BACKGROUND: Noonan syndrome, cardio-facio-cutaneous syndrome (CFC) and Costello syndrome constitute a group of developmental disorders with an overlapping pattern of congenital anomalies. Each of these conditions can be caused by germline mutations in key components of the highly conserved Ras-MAPK pathway, possibly reflecting a similar pathogenesis underlying the three disorders. Germline mutations in KRAS have recently been identified in a small number of patients with Noonan syndrome and CFC. METHODS AND RESULTS: 260 patients were screened for KRAS mutations by direct sequencing. Overall, we detected KRAS mutations in 12 patients, including three known and eight novel sequence alterations. All mutations are predicted to cause single amino acid substitutions. Remarkably, our cohort of individuals with KRAS mutations showed a high clinical variability, ranging from Noonan syndrome to CFC, and also included two patients who met the clinical criteria of Costello syndrome. CONCLUSION: Our findings reinforce the picture of a clustered distribution of disease associated KRAS germline alterations. We further defined the phenotypic spectrum associated with KRAS missense mutations and provided the first evidence of clinical differences in patients with KRAS mutations compared with Noonan syndrome affected individuals with heterozygous PTPN11 mutations and CFC patients carrying a BRAF, MEK1 or MEK1 alteration, respectively. We speculate that the observed phenotypic variability may be related, at least in part, to specific genotypes and possibly reflects the central role of K-Ras in a number of different signalling pathways.

Clinical and molecular characterization of two patients with overlapping de novo microdeletions in 2p14-p15 and mild mental retardation.

Here, we present two patients with overlapping de novo microdeletions in chromosome 2p14-p15, mild mental retardation concerning especially language development, as well as mild dysmorphic features. Patient 1 also presented with generalized seizures, sensorineural hearing loss, and relative microcephaly. In patient 1, molecular karyotyping detected a 2.23-Mb deletion in chromosome 2p14-p15 including 11 known genes. The second patient, with a 2.84-Mb microdeletion containing 15 genes, was identified in the DECIPHER database. The two deleted regions overlap by a stretch of 1.6 Mb that contains 10 genes, several of which have functions in neuronal development. This report illustrates the power of databases such as DECIPHER and MRNET in assessing the pathogenicity of copy-number variations (CNVs).

A novel microdeletion syndrome involving 5q14.3-q15: clinical and molecular cytogenetic characterization of three patients.

Molecular karyotyping is being increasingly applied to delineate novel disease causing microaberrations and related syndromes in patients with mental retardation of unknown aetiology. We report on three unrelated patients with overlapping de novo interstitial microdeletions involving 5q14.3-q15. All three patients presented with severe psychomotor retardation, epilepsy or febrile seizures, muscular hypotonia and variable brain and minor anomalies. Molecular karyotyping revealed three overlapping microdeletions measuring 5.7, 3.9 and 3.6 Mb, respectively. The microdeletions were identified using single nucleotide polymorphism (SNP) arrays (Affymetrix 100K and Illumina 550K) and array comparative genomic hybridization (1 Mb Sanger array-CGH). Confirmation and segregation studies were performed using fluorescence in situ hybridization (FISH) and quantitative PCR. All three aberrations were confirmed and proven to have occurred de novo. The boundaries and sizes of the deletions in the three patients were different, but an overlapping region of around 1.6 Mb in 5q14.3 was defined. It included five genes: CETN3, AC093510.2, POLR3G, LYSMD3 and the proximal part of GPR98/MASS1, a known epilepsy gene. Haploinsufficiency of GPR98/MASS1 is probably responsible for the seizure phenotype in our patients. At least one other gene contained in the commonly deleted region, LYSMD3, shows a high level of central nervous expression during embryogenesis and is also, therefore, a good candidate gene for other central nervous system (CNS) symptoms, such as psychomotor retardation, brain anomalies and muscular hypotonia of the 5q14.3 microdeletion syndrome.

Primary immunodeficiency in combination with transverse upper limb defect and anal atresia in a 34-year-old patient with Jacobsen syndrome.

We describe a 34-year-old male patient with Jacobsen syndrome associated with a broad spectrum of anomalies and an increased susceptibility to infections. Features commonly seen in Jacobsen syndrome were short stature, mental retardation, congenital heart disease, cryptorchidism, strabismus, distal hypospadia glandis, and mild thrombocytopenia. Chromosome analysis disclosed a mosaic 46,XY,del(11)(q24.1)/46,XY karyotype with a very low percentage of normal cells. In addition, transverse upper limb defect, imperforate anus, and hearing impairment were noted. Cellular anomalies include functional impairment and deficiency of T-helper cells, and a low serum immunoglobulin M (IgM)-level. The presence of a transverse limb defect and primary immunodeficiency has not been reported previously in Jacobsen syndrome.