BACKGROUND Increased secretion of growth hormone leads to gigantism in children and acromegaly in adults; the genetic causes of gigantism and acromegaly are poorly understood. METHODS We performed clinical and genetic studies of samples obtained from 43 patients with gigantism and then sequenced an implicated gene in samples from 248 patients with acromegaly. RESULTS We observed microduplication on chromosome Xq26.3 in samples from 13 patients with gigantism; of these samples, 4 were obtained from members of two unrelated kindreds, and 9 were from patients with sporadic cases. All the patients had disease onset during early childhood. Of the patients with gigantism who did not carry an Xq26.3 microduplication, none presented before the age of 5 years. Genomic characterization of the Xq26.3 region suggests that the microduplications are generated during chromosome replication and that they contain four protein-coding genes. Only one of these genes, GPR101, which encodes a G-protein–coupled receptor, was overexpressed in patients’ pituitary lesions. We identified a recurrent GPR101 mutation (p.E308D) in 11 of 248 patients with acromegaly, with the mutation found mostly in tumors. When the mutation was transfected into rat GH3 cells, it led to increased release of growth hormone and proliferation of growth hormone–producing cells. CONCLUSIONS We describe a pediatric disorder (which we have termed X-linked acrogigantism [X-LAG]) that is caused by an Xq26.3 genomic duplication and is characterized by early-onset gigantism resulting from an excess of growth hormone. Duplication of GPR101 probably causes X-LAG. We also found a recurrent mutation in GPR101 in some adults with acromegaly. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others.)

Unbalanced submicroscopic subtelomeric chromosomal rearrangements represent a significant cause of unexplained moderate to severe mental retardation with and without phenotypic abnormalities. We investigated 254 patients (102 from Zürich, 152 from Liège) for unbalanced subtelomeric rearrangements by using fluorescence in situ hybridisation with probes mapping to 41 subtelomeric regions. Mental retardation combined with a pattern of dysmorphic features, with or without major malformations, and growth retardation and a normal karyotype by conventional G-banding were the criteria of inclusion. Selection criteria were more restrictive for the Zürich series in terms of clinical and cytogenetic pre-investigation. We found 13 unbalanced rearrangements and two further aberrations, which, following the investigation of other family members, had to be considered as variants without influence on the phenotype. The significant aberrations included three de novo deletions (two of 1pter, one of 5pter), three de novo duplications (8pter, 9pter, Xpter), one de novo deletion 13qter-duplication 4qter, and five familial submicroscopic translocations [(1q;18p), (2q;4p), (2p;7q), (3p;22q), (4q;10q), (12p;22q)], most of them with several unbalanced offspring with deletion-duplication. Although the incidence of abnormal results was higher (10/152) in the Liège versus the Zürich series (3/102), similar selection criteria in Zürich as in Liège would have resulted in an incidence of 7/106 and thus similar figures. In our series, submicroscopic unbalanced rearrangements explain the phenotype in 13/254 study probands. The most important selection criterion seems to be the presence of more than one affected member in a family. An examination of subtelomeric segments should be included in the diagnostic work-up of patients with unexplained mental retardation combined with physical abnormalities, when a careful conventional examination of banded chromosomes has yielded a normal result and a thorough clinical examination does not lead to another classification. The proportion of abnormal findings depends strongly on selection criteria: more stringent selection can eliminate some examinations but necessitates a high workload for experienced clinical geneticists. Once the costs and workload of screening are reduced, less selective approaches might finally be more cost-effective.

We performed a multicentric study to assess the impact of two different culture procedures on the detection of chromosomal abnormalities in 217 consecutive unselected cases with chronic lymphocytic leukemia (CLL) referred for routine analysis either at the time of diagnosis (n = 172) or during disease evolution (n = 45). Parallel cultures of peripheral blood or bone marrow were set up with the addition of either the conventional B-cell mitogen 12-O-tetradecanoyl-phorbol-13-acetate (TPA) or a combination of CpG oligonucleotide (CpG) and interleukin-2 (IL-2). Cytogenetic analyses were performed on both cultures. Clonal abnormalities were identified in 116 cases (53%). In 78 cases (36%), the aberrant clone was detected in both cultures. Among these, the percentages of aberrant metaphases were similar in both conditions in 17 cases, higher in the CpG/IL-2 culture in 43 cases, and higher in the TPA culture in 18 cases. Clonal aberrations were detected in only one culture, either in CpG/IL-2 or TPA in 33 (15%) and 5 (2%) cases, respectively. Taken together, abnormal karyotypes were observed in 51% with CpG/IL-2 and 38% with TPA (P < 0.0001). Application of FISH (n = 201) allowed the detection of abnormalities not visible by conventional cytogenetic analysis in 80 cases: del(13q) (n = 71), del(11q) (n = 5), +12 (n = 2), del(14q) (n = 1), and del(17p) (n = 1). In conclusion, our results confirm that CpG/IL-2 stimulation increases the detection rate of chromosomal abnormalities in CLL compared with TPA and that further improvement can be obtained by FISH. However, neither conventional cytogenetics nor FISH detected all aberrations, demonstrating the complementary nature of these techniques.

Objective With the replacement of karyotyping by chromosomal microarray (CMA) in invasive prenatal diagnosis, new challenges have arisen. By building a national database, we standardize the classification and reporting of prenatally detected copy number variants (CNVs) across Belgian genetic centers. This database, which will link genetic and ultrasound findings with postnatal development, forms a unique resource to investigate the pathogenicity of variants of uncertain significance and to refine the phenotypic spectrum of pathogenic and susceptibility CNVs. Methods The Belgian MicroArray Prenatal (BEMAPRE) consortium is a collaboration of all genetic centers in Belgium. We collected data from all invasive prenatal procedures performed between May 2013 and July 2016. Results In this three‐year period, 13 266 prenatal CMAs were performed. By national agreement, a limited number of susceptibility CNVs and no variants of uncertain significance were reported. Added values for using CMA versus conventional karyotyping were 1.8% in the general invasive population and 2.7% in cases with an ultrasound anomaly. Of the reported CNVs, 31.5% would have remained undetected with non‐invasive prenatal test as the first‐tier test. Conclusion The establishment of a national database for prenatal CNV data allows for a uniform reporting policy and the investigation of the prenatal and postnatal genotype–phenotype correlation.

To describe a patient who developed a youngonset, dopa-responsive parkinsonism linked to a de novo heterozygous interstitial duplication 4q.