A French collaborative survey of 272 fetuses with 22q11.2 deletion: ultrasound findings, fetal autopsies and pregnancy outcomes.

OBJECTIVE: The 22q11.2 deletion (del22q11.2) is one of the most common microdeletions. We performed a collaborative, retrospective analysis in France of prenatal diagnoses and outcomes of fetuses carrying the del22q11.2. METHODS: A total of 272 fetuses were included. Data on prenatal diagnosis, ultrasound findings, pathological features, outcomes and inheritance were analyzed. RESULTS: The mean time of prenatal diagnosis was 25.6 ± 6 weeks of gestation. Most of the diagnoses (86.8%) were prompted by abnormal ultrasound findings [heart defects (HDs), in 83.8% of cases]. On fetal autopsy, HDs were again the most common disease feature, but thymus, kidney abnormalities and facial dysmorphism were also described. The deletion was inherited in 27% of cases. Termination of pregnancy (TOP) occurred in 68.9% of cases and did not appear to depend on the inheritance status. However, early diagnosis was associated with a higher TOP rate. CONCLUSION: This is the largest cohort of prenatal del22q11.2 diagnoses. As in postnatally diagnosed cases, HDs were the most frequently observed abnormalities. However, thymus and kidney abnormalities and polyhydramnios should also be screened for in the prenatal diagnosis of del22q11.2. Only the time of diagnosis appeared to be strongly associated with the pregnancy outcome: the earlier the diagnosis, the higher the TOP rate.

A novel microdeletion syndrome at 3q13.31 characterised by developmental delay, postnatal overgrowth, hypoplastic male genitals, and characteristic facial features.

BACKGROUND: Congenital deletions affecting 3q11q23 have rarely been reported and only five cases have been molecularly characterised. Genotype-phenotype correlation has been hampered by the variable sizes and breakpoints of the deletions. In this study, 14 novel patients with deletions in 3q11q23 were investigated and compared with 13 previously reported patients. METHODS: Clinical data were collected from 14 novel patients that had been investigated by high resolution microarray techniques. Molecular investigation and updated clinical information of one cytogenetically previously reported patient were also included. RESULTS: The molecular investigation identified deletions in the region 3q12.3q21.3 with different boundaries and variable sizes. The smallest studied deletion was 580 kb, located in 3q13.31. Genotype-phenotype comparison in 24 patients sharing this shortest region of overlapping deletion revealed several common major characteristics including significant developmental delay, muscular hypotonia, a high arched palate, and recognisable facial features including a short philtrum and protruding lips. Abnormal genitalia were found in the majority of males, several having micropenis. Finally, a postnatal growth pattern above the mean was apparent. The 580 kb deleted region includes five RefSeq genes and two of them are strong candidate genes for the developmental delay: DRD3 and ZBTB20. CONCLUSION: A newly recognised 3q13.31 microdeletion syndrome is delineated which is of diagnostic and prognostic value. Furthermore, two genes are suggested to be responsible for the main phenotype.

Microdeletion at chromosome 4q21 defines a new emerging syndrome with marked growth restriction, mental retardation and absent or severely delayed speech.

BACKGROUND Genome-wide screening of large patient cohorts with mental retardation using microarray-based comparative genomic hybridisation (array-CGH) has recently led to identification several novel microdeletion and microduplication syndromes. METHODS Owing to the national array-CGH network funded by the French Ministry of Health, shared information about patients with rare disease helped to define critical intervals and evaluate their gene content, and finally determine the phenotypic consequences of genomic array findings. RESULTS In this study, nine unrelated patients with overlapping de novo interstitial microdeletions involving 4q21 are reported. Several major features are common to all patients, including neonatal muscular hypotonia, severe psychomotor retardation, marked progressive growth restriction, distinctive facial features and absent or severely delayed speech. The boundaries and the sizes of the nine deletions are different, but an overlapping region of 1.37 Mb is defined; this region contains five RefSeq genes: PRKG2, RASGEF1B, HNRNPD, HNRPDL and ENOPH1. DISCUSSION Adding new individuals with similar clinical features and 4q21 deletion allowed us to reduce the critical genomic region encompassing two genes, PRKG2 and RASGEF1B. PRKG2 encodes cGMP-dependent protein kinase type II, which is expressed in brain and in cartilage. Information from genetically modified animal models is pertinent to the clinical phenotype. RASGEF1B is a guanine nucleotide exchange factor for Ras family proteins, and several members have been reported as key regulators of actin and microtubule dynamics during both dendrite and spine structural plasticity. CONCLUSION Clinical and molecular delineation of 4q21 deletion supports a novel microdeletion syndrome and suggests a major contribution of PRKG2 and RASGEF1B haploinsufficiency to the core phenotype.