Purpose: Deletions of distal 9p are associated with trigonocephaly, mental retardation, dysmorphic facial features, cardiac anomalies, and abnormal genitalia. Previous studies identified a proposed critical region for the consensus phenotype in band 9p23, between 11.8 Mb and 16 Mb from the 9p telomere. Here we report 10 new patients with 9p deletions; 9 patients have clinical features consistent with 9pϪ syndrome, but possess terminal deletions smaller than most reported cases, whereas one individual lacks the 9pϪ phenotype and shows a 140-kb interstitial telomeric deletion inherited from his mother. Methods: We combined fluorescence in situ hybridization and microarray analyses to delineate the size of each deletion. Results: The deletion sizes vary from 800 kb to 12.4 Mb in our patients with clinically relevant phenotypes. Clinical evaluation and comparison showed little difference in physical features with regard to the deletion sizes. Severe speech and language impairment were observed in all patients with clinically relevant phenotypes. Conclusion: The smallest deleted region common to our patients who demonstrate a phenotype consistent with 9pϪ is Ͻ2 Mb of 9pter, which contains six known genes.These genes may contribute to some of the cardinal features of 9p deletion syndrome. Genet Med 2008:10 (8): 599 -611. Key Words: 9p deletion, FISH, genotype-phenotype correlation, aCGHThe 9p deletion syndrome is characterized by trigonocephaly, moderate to severe mental retardation, low-set, malformed ears, and dysmorphic facial features, such as up-slanting palpebral fissures and a long philtrum. 1,2 Furthermore, abnormal genitalia are found in some 9pϪ patients who have a chromosomal complement of 46, XY, 3 and hypopigmentation has also been described in two independent studies. 4,5 Since the original report of the syndrome in 1973, 6 over 140 cases of 9p deletion have been documented. The breakpoints occur in bands from 9p22 to 9p24, and the large majority of patients have either terminal deletions or translocations involving another chromosome.Previous studies have delineated the size of 9p deletions in an attempt to develop genotype-phenotype correlations. In one large study, Christ et al., 2 characterized the deletion breakpoints in 24 patients with visible 9p deletions and breakpoints at 9p22 or 9p23. Markers D9S274 (14.2 Mb from the telomere) and D9S286 (8 Mb) were absent in all 24 patients with 9pϪ, whereas D9S285 (16 Mb) was present in a subset of these patients. Thus, the minimal deleted segment in this group of patients included 16 Mb of the 9p terminus. Wagstaff and Hemann 4 described a patient with typical features of 9pϪsyndrome and an interstitial deletion between 8 Mb and 19 Mb of 9p. Based on the data of Wagstaff and Hemann, 4 and from their own data, Christ et al., 2 modified their critical region, i.e., the distal 16 Mb of 9p, and concluded that the critical region for the 9pϪsyndrome lies in an ϳ8-Mb region between D9S285 and D9S286, encompassing bands 9p22-9p23.Among a number of recent publicati...

Cryptic telomere deletions have been proposed to be a significant cause ofidiopathic mental retardation. We present two unrelated subjects, with normal G banding analysis, in whom 22q telomere deletions were serendipitously detected at two different institutions using fluorescence in situ hybridisation (FISH). Both probands presented with several of the previously described features associated with 22q deletions, including hypotonia, developmental delay, and absence of speech. Our two cases increase the total number of reported 22q telomere deletions to 19, the majority of which were identified by cytogenetic banding analysis. With the limited sensitivity of routine cytogenetic studies (-2-5 Mb), these two new cases suggest that the actual prevalence of 22q telomere deletions may be higher than currentiy documented. Of additional interest is the phenotypic overlap with Angelman syndrome (AS) as it raises the possibility of a 22q deletion in patients in whom AS has been ruled out. The use oftelomeric probes as diagnostic reagents would be useful in determining an accurate prevalence of chromosome 22q deletions and could result in a significantiy higher detection rate of subtelomeric rearrangements.

Short-rib polydactyly syndromes (SRPS) and Asphyxiating thoracic dystrophy (ATD) or Jeune Syndrome are recessively inherited skeletal ciliopathies characterized by profound skeletal abnormalities and are frequently associated with polydactyly and multiorgan system involvement. SRPS are produced by mutations in genes that participate in the formation and function of primary cilia and usually result from disruption of retrograde intraflagellar (IFT) transport of the cilium. Herein we describe a new spectrum of SRPS caused by mutations in the gene IFT81, a key component of the IFT-B complex essential for anterograde transport. In mutant chondrocytes, the mutations led to low levels of IFT81 and mutant cells produced elongated cilia, had altered hedgehog signaling, had increased post-translation modification of tubulin, and showed evidence of destabilization of additional anterograde transport complex components. These findings demonstrate the importance of IFT81 in the skeleton, its role in the anterograde transport complex, and expand the number of loci associated with SRPS.

A case of fetal Pfeiffer's syndrome is presented, showing the contribution of three dimensional (3D) sonography in the diagnosis of craniosynostosis--a major feature of this syndrome.

We report the first case of maternal uniparental disomy for chromosome 6 (UPD6mat) ascertained through congenital adrenal hyperplasia (CAH), which arose because of reduction to homozygosity of an autosomal recessive mutation. This case suggests that UPD6mat is associated with intrauterine growth retardation (IUGR). A case of paternal UPD (involving only the short arm of chromosome 6) ascertained as CAH has previously been reported, but was not stated to have IUGR. Our patient was born with IUGR followed by extraordinarily good catch-up growth. She had a history of a marked lag in motor development. She presented at 2.65 y of age with pubarche of 3 mo duration, clitoral enlargement, and an advanced bone age. Simple virilizing CAH was diagnosed by elevations of plasma 17-hydroxyprogesterone and testosterone. Mutation analysis showed that the CAH was due to homozygosity for the 1172N exon 4 mutation. When parental DNA was examined, the mother was found to be heterozygous for the uncommon exon 4 mutation, while the father had no detectable mutations. DNA microsatellite analysis was subsequently performed on the patient and parents using polymorphic markers spanning the entire chromosome 6. Seven markers were informative for inheritance of a single maternal allele and absence of paternal alleles in the proband. Analysis of microsatellite markers from other chromosomes confirmed biparental inheritance at these loci. This combination of findings is diagnostic of UPD6mat. The only other reported case of UPD6mat was discovered serendipitously when genotyped for renal transplantation; this patient had a history of IUGR. Since both cases of UPD6mat had IUGR, the phenotype appears to include IUGR as well as the potential to unmask an autosomal recessive trait.