Judy Chernos

Microduplication and triplication of 22q11.2: a highly variable syndrome.

22q11.2 microduplications of a 3-Mb region surrounded by low-copy repeats should be, theoretically, as frequent as the deletions of this region; however, few microduplications have been reported. We show that the phenotype of these patients with microduplications is extremely diverse, ranging from normal to behavioral abnormalities to multiple defects, only some of which are reminiscent of the 22q11.2 deletion syndrome. This diversity will make ascertainment difficult and will necessitate a rapid-screening method. We demonstrate the utility of four different screening methods. Although all the screening techniques give unique information, the efficiency of real-time polymerase chain reaction allowed the discovery of two 22q11.2 microduplications in a series of 275 females who tested negative for fragile X syndrome, thus widening the phenotypic diversity. Ascertainment of the fragile X-negative cohort was twice that of the cohort screened for the 22q11.2 deletion. We also report the first patient with a 22q11.2 triplication and show that this patients mother carries a 22q11.2 microduplication. We strongly recommend that other family members of patients with 22q11.2 microduplications also be tested, since we found several phenotypically normal parents who were carriers of the chromosomal abnormality.

Analysis of sperm chromosome complements from a man heterozygous for a pericentric inversion of chromosome 1

Human sperm chromosomes were studied in a man heterozygous for a pericentric inversion of chromosome (1)(p31q12). Q-banded pronuclear chromosomes were analyzed after in vitro penetration of golden hamster oocytes. A total of 159 sperm were examined: 54% bearing the inverted chromosome 1 and 46% the normal chromosome 1. These frequencies are not significantly different from the theoretical 1∶1 ratio. There were no recombinant sperm with duplications or deficiencies, suggesting that a pairing loop failed to form or that crossing-over was suppressed. The frequency of abnormalities unrelated to the inversion was 5% for numerical, 8.8% for structural, 2.5% for numerical and structural, values not significantly different from control donors studied in our lab. The frequencies of X- and Y-bearing sperm were 46% and 54%, respectively, not significantly different from the expected value of 50%. This is the fifth pericentric inversion studied by human sperm chromosome analysis; recombinant chromosomes have been observed in two of the five cases. Some of the factors associated with an increased risk of recombinant sperm appear to be inversion size greater than 30% of the chromosome and chromosome breakpoints in G-light bands.

CCMG guidelines: prenatal and postnatal diagnostic testing for uniparental disomy

Dawson AJ, Chernos J, McGowan‐Jordan J, Lavoie J, Shetty S, Steinraths M, Wang J‐C, Xu J. CCMG guidelines: prenatal and postnatal diagnostic testing for uniparental disomy.

Cri du chat syndrome due to meiotic recombination in a pericentric inversion 5 carrier

A female infant presented at birth with hypotonia, growth retardation, distinctive facies, multiple congenital anomalies, and a high‐pitched mewing cry characteristic of cri du chat syndrome. Chromosome studies from both peripheral blood and fibroblasts showed a 46,XX,5p–karyotype. Parental chromosome studies revealed that the mother carried an apparently balanced pericentric inversion of one chromosome no. 5, 46,XX,inv(5)(pl4q35). Meiotic crossing‐over in the mother within the inverted segment of chromosome 5 gave rise to the unbalanced karyotype, 46,XX,rec(5)dup q, inv(5)(pl4q35)mat in the infant. A small terminal segment of the long arm of chromosome 5 (q35‐pter) is duplicated with a deletion of the short arm of chromosome 5 (pl4‐pter), accounting for the features of cri du chat syndrome. Fewer than 1 in 200 of cri du chat syndrome cases are due to recombination aneusomy arising from a parental inversion of chromosome 5. Some of these cases, however, do not have typical cri du chat syndrome, reflecting significant duplication of 5q material. These cases are reviewed with the present case, and recombination behaviour leading to chromosome imbalance is discussed.

Mosaic trisomy 1q: a recurring chromosome anomaly that is a diagnostic challenge and is associated with a Fryns‐like phenotype

Trisomy of the long arm of chromosome 1 is a very rare cytogenetic anomaly that is difficult to diagnose because of tissue‐limited mosaicism. This study aimed to further characterize the prenatal and post‐natal findings associated with this anomaly, including the first reported chromosomal microarray finding.

A 2q24.3q31.1 microdeletion found in a patient with Filippi-like syndrome phenotype: a case report.

Filippi syndrome is characterized by developmental delay, growth failure, cryptorchidism, bilateral hand and foot syndactyly, and facial dysmorphism. The 2q24q31 contiguous deletion syndrome has similarly been associated with hand and foot anomalies, growth retardation, microcephaly, characteristic facies with a broad prominent nasal root and thin alae nasi, and intellectual disability. We present a patient with this deletion who has a Filippi‐like phenotype, which may be the first causative cytogenetic result in this syndrome. This suggests the importance of array comparative genomic hybridization in evaluation of patients with Filippi syndrome, and suggests that the inheritance may not always be autosomal recessive.

Prenatal Array Comparative Genomic Hybridization in Fetuses With Structural Cardiac Anomalies.

OBJECTIVESnTo examine the diagnostic performance of array comparative genomic hybridization (CGH) for fetal cardiac anomalies in two medium-sized Canadian prenatal genetics clinics.nnnMETHODSnWe prospectively recruited 22 pregnant women with fetal structural cardiac anomalies, normal rapid aneuploidy detection, and FISH for 22q11.2 testing for array CGH analysis.nnnRESULTSnOne case had an 8p deletion that was also visible on karyotype and included the GATA4 gene, which has been associated with congenital heart disease. Two cases had inherited pathogenic copy number variants (CNVs) of variable expressivity and penetrance: one was a duplication of 16p11.2 and the other a deletion of 15q11.2. One case had the incidental finding of being a carrier of a recessive disease unrelated to the cardiac anomaly.nnnCONCLUSIONSnOf these prospectively recruited cases of fetal cardiac anomalies, 14% had a pathogenic result on array CGH. Pathogenic CNVs of variable penetrance and expressivity were a significant proportion of the positive results identified. These CNVs are generally associated with neurodevelopmental issues and may or may not have been associated with the fetus underlying congenital heart disease. Array CGH increases the diagnostic yield in this group of patients; however, certain CNVs remain a challenge for counselling in the prenatal setting.

MG-140 17Q21.31 microdeletion syndrome: A description of two cases

17q21.31 microdeletion syndrome, also known as Koolen-De Vries syndrome, commonly involves a 500- to 650-kb heterozygous deletion and has a possible incidence of 1 in 16,000. The most frequent clinical features include distinctive facial features, significant speech delays with mild global developmental delays (GDD), childhood hypotonia, congenital malformations, and a friendly disposition. Here we report two patients with 17q21.31 microdeletion syndrome referred for evaluation by metabolic genetics. Both patients were referred at approximately two and a half years of age for evaluation of lysosomal storage disease in view of presumed plateauing in speech development, GDD, and coarse and dysmorphic facial features. Patient one also had seizures and laryngomalacia. She was found to carry a 987.4 kb deletion, the largest described in the literature to our knowledge, extending distally to partially include the gene NSF (Figure 1). Patient two also had hip dysplasia and mild hypotonia. She was found to carry a 695.5 kb deletion (Figure 2).Abstract MG-140 Figure 1Abstract MG-140 Figure 2 By presenting these two cases, we hope to add to the phenotype of 17q21.31 microdeletion syndrome and to outline the importance of considering comparative genomic hybridization in patients initially suspected to have inborn errors of metabolism.