Context: Homozygous IGF1 deletions or mutations lead to severe short stature, deafness, microcephaly, and mental retardation. Heterozygosity for an IGF-1 defect may modestly decrease height and... Show moreContext: Homozygous IGF1 deletions or mutations lead to severe short stature, deafness, microcephaly, and mental retardation. Heterozygosity for an IGF-1 defect may modestly decrease height and head circumference. Objective: The objective of the study was to investigate the clinical features of heterozygous carriers of a novel mutation in the IGF1 gene in comparison with noncarriers in a short family and to establish the effect of human GH treatment. Subjects: Two children, their mother, and their maternal grandfather carried the mutation and were compared with two relatives who were noncarriers. Results: The two index cases had severe short stature (height SD score -4.1 and -4.6), microcephaly, and low IGF-1 levels. Sequencing of IGF1 revealed a heterozygous duplication of four nucleotides, resulting in a frame shift and a premature termination codon. The mother and maternal grandfather had the same IGF1 mutation. Adult height (corrected for shrinking and secular trend) and head circumference SD score of carriers of the paternally transmitted mutation was -2.5 and -1.8, in comparison with -1.6 and 0.3 in noncarriers, respectively. After 2yr of GH treatment, both index cases exhibited increased growth. Conclusions: Heterozygosity for this novel IGF1 mutation in children born from a mother with the same mutation, presumably in combination with other genetic factors for short stature, leads to severe short stature, which can be successfully treated with GH. (J Clin Endocrinol Metab 95: E363-E367, 2010) Show less
Apparently balanced chromosome abnormalities are occasionally associated with mental retardation (MR). These balanced rearrangements may disrupt genes. However, the phenotype may also be caused by... Show moreApparently balanced chromosome abnormalities are occasionally associated with mental retardation (MR). These balanced rearrangements may disrupt genes. However, the phenotype may also be caused by small abnormalities present at the breakpoints or elsewhere in the genome. Conventional karyotyping is not instrumental for detecting small abnormalities because it only identifies genomic imbalances larger than 5-10 Mb. In contrast, high-resolution whole-genome arrays enable the detection of submicroscopic abnormalities in patients with apparently balanced rearrangements. Here, we report on the whole-genome analysis of 13 MR patients with previously detected balanced chromosomal abnormalities, five de novo, four inherited, and four of unknown inheritance, using Single Nucleotide Polymorphism (SNP) arrays. In all the cases, the patient had an abnormal phenotype. In one familial case and one unknown inheritance case, one of the parents had a phenotype which appeared identical to the patient's phenotype. Additional copy number variants (CNVs) were identified in eight patients. Three patients contained CNVs adjacent to one or either breakpoints. One of these patients showed four and two deletions near the breakpoints of a de novo pericentric inversion. In five patients we identified CNVs on chromosomes unrelated to the previously observed genomic imbalance. These data demonstrate that high-resolution array screening and conventional karyotyping is necessary to tie complex karyotypes to phenotypes of MR patients. (C) 2010 Elsevier Masson SAS. All rights reserved. Show less
We report a 797 kb de novo interstitial deletion of 18q21.31 in a 6-year-old boy with speech delay, mental retardation, sleeping problems, facial dysmorphism, and feet anomalies. Examination of the... Show moreWe report a 797 kb de novo interstitial deletion of 18q21.31 in a 6-year-old boy with speech delay, mental retardation, sleeping problems, facial dysmorphism, and feet anomalies. Examination of the region showed two genes, TXNL1 and WDR7, to be involved in the deletion. Haploinsufficiency of these genes could potentially contribute to the phenotype. Our patient has some clinical features that overlap with earlier described patients with a larger deletion of the distal part of chromosome 18q. The small deletion in region 18q21.31 may be responsible for some of the common features found in patients with larger 18q deletions. Show less
Here we report the clinical and cytogenetic results of a family carrying a cryptic translocation involving chromosome 3pter and 21qter detected by single nucleotide polymorphism array and... Show moreHere we report the clinical and cytogenetic results of a family carrying a cryptic translocation involving chromosome 3pter and 21qter detected by single nucleotide polymorphism array and subtelomeric fluorescent in situ hybridisation analysis. The index patient, with mild mental retardation in combination with minor dysmorphic features, inherited the derivative chromosome 21 resulting in a partial trisomy of the short arm of chromosome 3 and a partial monosomy of the long arm of chromosome 21. Her apparently healthy brother inherited the derivative chromosome 3 resulting in a terminal deletion of the short arm of chromosome 3 and a terminal duplication of the long arm of chromosome 21. We discuss the different phenotypes for the 2 genotypes and argue for the importance of reporting these imbalances to achieve accurate genetic counseling in prenatal and postnatal diagnosis. Show less
The most common mutations found in FBN1 are missense mutations (56%), mainly substituting or creating a cysteine in a cbEGF domain. Other mutations are frameshift, splice and nonsense mutations.... Show moreThe most common mutations found in FBN1 are missense mutations (56%), mainly substituting or creating a cysteine in a cbEGF domain. Other mutations are frameshift, splice and nonsense mutations. There are only a few reports of patients with marfanoid features and a molecularly proven complete deletion of a FBN1 allele. We describe the clinical features of 10 patients with a complete FBN1 gene deletion. Seven patients fulfilled the Ghent criteria for Marfan syndrome (MFS). The other three patients were examined at a young age and did not (yet) present the full clinical picture of MFS yet. Ectopia lentis was present in at least two patients. Aortic root dilatation was present in 6 of the 10 patients. In three patients, the aortic root diameter was on the 95th percentile and in one patient, the diameter of the aortic root was normal, the cross-section, however, had a cloverleaf appearance. Two patients underwent aortic root surgery at a relatively young age (27 and 34 years). Mitral valve prolapse was present in 4 of the 10 patients, and billowing of the mitral valve in 1. All patients had facial and skeletal features of MFS. Two patients with a large deletion extending beyond the FBN1 gene had an extended phenotype. We conclude that complete loss of one FBN1 allele does not predict a mild phenotype, and these findings support the hypothesis that true haploinsufficiency can lead to the classical phenotype of Marfan syndrome. Show less
Constitutional chromosomal aberrations are inborn changes with or without phenotypic consequences. Conventional chromosome analysis has been for a long time the method of choice for identification... Show moreConstitutional chromosomal aberrations are inborn changes with or without phenotypic consequences. Conventional chromosome analysis has been for a long time the method of choice for identification of such abnormalities. However, over the past decades, several molecular cytogenetic techniques have successfully been introduced into the genetic diagnostic laboratories to increase the detection sensitivity and to outline chromosome rearrangements in more detail. Each method has its strength and limitation, therefore often several techniques are needed to detect and unravel the complexity of chromosome abnormalities. This chapter focuses on the most commonly used methods in the diagnostic setting for detection and characterization of constitutional chromosome abnormalities. Show less
