Clinical features of trisomy 12 mosaicism-Report and review.

Trisomy 12 mosaicism is a rare condition. Herein, we report a patient with mosaic trisomy 12 who was conceived by in vitro fertilization. She presented with mild dysmorphic features at birth, including down-slanting palpebral fissures, a depressed and creased nasal bridge, and mild rhizomelic shortening of the limbs. She had age-appropriate development at 6 months of age, but displayed slightly more dysmorphic features than at birth. Chromosome analysis on peripheral blood revealed a normal female karyotype in 50 metaphases. A concurrent genomic microarray analysis showed trisomy 12 in about 25% of the specimen, which was also confirmed by fluorescence in situ hybridization analysis with the CEP12 probe. Our findings further delineate the clinical features in trisomy 12 mosaicism in liveborns and demonstrate the utility of genomic microarray analysis in identification of mosaic aneuploidies.

SCRIB and PUF60 are primary drivers of the multisystemic phenotypes of the 8q24.3 copy-number variant.

Copy-number variants (CNVs) represent a significant interpretative challenge, given that each CNV typically affects the dosage of multiple genes. Here we report on five individuals with coloboma, microcephaly, developmental delay, short stature, and craniofacial, cardiac, and renal defects who harbor overlapping microdeletions on 8q24.3. Fine mapping localized a commonly deleted 78 kb region that contains three genes: SCRIB, NRBP2, and PUF60. In vivo dissection of the CNV showed discrete contributions of the planar cell polarity effector SCRIB and the splicing factor PUF60 to the syndromic phenotype, and the combinatorial suppression of both genes exacerbated some, but not all, phenotypic components. Consistent with these findings, we identified an individual with microcephaly, short stature, intellectual disability, and heart defects with a de novo c.505C>T variant leading to a p.His169Tyr change in PUF60. Functional testing of this allele in vivo and in vitro showed that the mutation perturbs the relative dosage of two PUF60 isoforms and, subsequently, the splicing efficiency of downstream PUF60 targets. These data inform the functions of two genes not associated previously with human genetic disease and demonstrate how CNVs can exhibit complex genetic architecture, with the phenotype being the amalgam of both discrete dosage dysfunction of single transcripts and also of binary genetic interactions.

Mutations in the glycosylphosphatidylinositol gene PIGL cause CHIME syndrome.

CHIME syndrome is characterized by colobomas, heart defects, ichthyosiform dermatosis, mental retardation (intellectual disability), and ear anomalies, including conductive hearing loss. Whole-exome sequencing on five previously reported cases identified PIGL, the de-N-acetylase required for glycosylphosphatidylinositol (GPI) anchor formation, as a strong candidate. Furthermore, cell lines derived from these cases had significantly reduced levels of the two GPI anchor markers, CD59 and a GPI-binding toxin, aerolysin (FLAER), confirming the pathogenicity of the mutations.

A novel dominant negative mutation of OTX2 associated with combined pituitary hormone deficiency.

CONTEXT: Combined pituitary hormone deficiency (CPHD) is characterized by deficiencies in more than one anterior pituitary hormone. Mutations in developmental factors responsible for pituitary cell specification and gene expression have been found in CPHD patients. OTX2, a bicoid class homeodomain protein, is necessary for both forebrain development and transactivation of the HESX1 promoter, but as of yet, has not been associated with CPHD. OBJECTIVE: The goal of this study was to identify and characterize novel mutations in pituitary specific transcription factors from CPHD patients. DESIGN: Genomic DNA was isolated from patients with hypopituitarism to amplify and sequence eight pituitary specific transcription factors (HESX1, LHX3, LHX4, OTX2, PITX2, POU1F1, PROP1, and SIX6). Characterization of novel mutations is based on structural and functional studies. RESULTS: We describe two unrelated children with CPHD who presented with neonatal hypoglycemia, and deficiencies of GH, TSH, LH, FSH, and ACTH. Magnetic resonance imaging revealed anterior pituitary hypoplasia with an ectopic posterior pituitary. A novel heterozygous OTX2 mutation (N233S) was identified. Wild-type and mutant OTX2 proteins bind equivalently to bicoid binding sites, whereas mutant OTX2 revealed decreased transactivation. CONCLUSIONS: A novel mutation in OTX2 binds normally to target genes and acts as a dominant negative inhibitor of HESX1 gene expression. This suggests that the expression of HESX1, required for spaciotemporal development of anterior pituitary cell types, when disrupted, results in an absent or underdeveloped anterior pituitary with diminished hormonal expression. These results demonstrate a novel mechanism for CPHD and extend our knowledge of the spectrum of gene mutations causing CPHD.

A child with deletion (14)(q24.3q32.13) and auditory neuropathy.

An interstitial deletion in the middle and distal part of chromosome 14 is a rare chromosomal abnormality characterized by a wide spectrum of phenotypic manifestations. We present a patient with a nearly 20 Mb interstitial deletion of chromosome 14q24.3q32.13 determined by FISH, that is associated with minor dysmorphic features, developmental delay, absent speech and auditory neuropathy. The deleted region contains 130 known genes, among them 48 with reported function or association with human disease. The patient's phenotype is compared with interstitial deletions of the distal part of chromosome 14 reported previously. We hypothesize, that there is (are) a gene (genes) in the 14q32.11-q32.13 that is (are) important for the hearing process and for which haploinsufficiency can cause auditory neuropathy. Several genes in the region, among them calmodulin, chromogranin A, the goosecoid and FOXN3, can contribute to the observed phenotype. Detailed mapping in additional patients with 14q32 deletions and hearing loss could further define the candidate region.

Familial interstitial duplication of 11q; partial trisomy (11)(q13.5q21).

We report on a case of an interstitial duplication of 11q in a patient with developmental delay and in his moderately delayed mother. Partial trisomy 11q is well documented in the literature with most cases involving the distal region of the long arm of chromosome 11. In almost all cases, this trisomy is associated with monosomy of the second chromosome involved in the parental translocation. The most common, partial 11q and 22q trisomy syndrome, is observed in offspring of t(11;22)(q23;q11.2) carriers from a 3:1 tertiary trisomic malsegregation. We found only two previous reports of pure partial trisomy 11q in the literature. Comparison of the clinical findings of our patient and another single published report of duplication in the same segment of chromosome 11 suggests that the duplication of this region manifests mild phenotypic abnormalities.