12q14 microdeletion associated with HMGA2 gene disruption and growth restriction.

The 12q14 microdeletion syndrome is a rare condition that has previously been characterized by pre- and postnatal growth restriction, proportionate short stature, failure to thrive, developmental delay, and osteopoikilosis. Previously reported microdeletions within this region have ranged in size from 1.83 to 10.12 Mb with a proposed 2.61 Mb smallest region of overlap containing the LEMD3, HMGA2, and GRIP1 genes. Here, we report on the identification of a 12q14 microdeletion in a female child presenting with proportionate short stature, failure to thrive, and speech delay. The genomic loss (minimum size 4.17 Mb, maximum size 4.21 Mb) contained 25 RefSeq genes including IRAK3, GRIP1, and the 3' portion of the HMGA2 gene. This is the first partial deletion of HMGA2 associated with the 12q14 microdeletion syndrome. This case further clarifies the association of LEMD3 deletions with the 12q14 microdeletion syndrome and provides additional support for the role of the HMGA2 gene in human growth.

Mutations in PYCR1 cause cutis laxa with progeroid features.

Autosomal recessive cutis laxa (ARCL) describes a group of syndromal disorders that are often associated with a progeroid appearance, lax and wrinkled skin, osteopenia and mental retardation. Homozygosity mapping in several kindreds with ARCL identified a candidate region on chromosome 17q25. By high-throughput sequencing of the entire candidate region, we detected disease-causing mutations in the gene PYCR1. We found that the gene product, an enzyme involved in proline metabolism, localizes to mitochondria. Altered mitochondrial morphology, membrane potential and increased apoptosis rate upon oxidative stress were evident in fibroblasts from affected individuals. Knockdown of the orthologous genes in Xenopus and zebrafish led to epidermal hypoplasia and blistering that was accompanied by a massive increase of apoptosis. Our findings link mutations in PYCR1 to altered mitochondrial function and progeroid changes in connective tissues.

Atypical X-chromosome inactivation in an X;1 translocation patient demonstrating Xq28 functional disomy.

X-chromosome inactivation (XCI) is an epigenetic process used to regulate gene dosage in mammalian females by silencing genes on one X-chromosome. While the pattern of XCI is typically random in normal females, abnormalities of the X-chromosome may result in skewing due to disadvantaged cell growth. We describe a female patient with an X;1 translocation [46,X,t(X;1)(q28;q21)] and unusual pattern of XCI who demonstrates functional disomy of the Xq28 region distal to the translocation breakpoint. There was complete skewing of XCI in the patient, along with the atypical findings of an active normal X chromosome and an inactive derivative X. Characterization of the translocation revealed that the patient's Xq28 breakpoint interrupts the DKC1 gene. Molecular analysis of the breakpoint region revealed functional disomy of Xq28 genes distal to DKC1. We propose that atypical XCI occurred in the patient due to a post-inactivation cell selection mechanism likely initiated by disruption of DKC1. As a result, the pattern of XCI is opposite that of the expected for an X;autosome translocation. Therefore, we suggest the phenotypic abnormalities found in the patient are a result of functional disomy in the Xq28 region.

Cornelia de Lange syndrome: clinical review, diagnostic and scoring systems, and anticipatory guidance.

Cornelia de Lange syndrome (CdLS), also known as Brachmann-de Lange syndrome, is a well-described multiple malformation syndrome typically involving proportionate small stature, developmental delay, specific facial features, major malformations (particularly the cardiac, gastrointestinal and musculoskeletal systems), and behavioral abnormalities. There is a broad spectrum of clinical involvement, with increasing recognition of a much milder phenotype than previously recognized. Significant progress has been made in recent years in the clinical and molecular delineation of CdLS, necessitating a revision of the diagnostic criteria, more inclusive of the milder cases. In addition, a scoring system of severity has been found to correlate with specific brain changes. Thus, a clinical overview and recommendations for anticipatory guidance are timely in aiding caretakers and professionals to individualize care decisions and maximize developmental potential for individuals with CdLS. These guidelines are derived from consensus based on collective experience of over 500 patients with CdLS, observations of the natural history in children, adolescents, and adults, a review of the literature, and contacts with national support organizations in North America and Europe.

Increasing knowledge of PTEN germline mutations: Two additional patients with autism and macrocephaly.

Recently, Butler et al. [2005; J Med Genet 42:318-321] reported the presence of heterozygous germline mutations in the PTEN tumor suppressor gene in three children with autism and macrocephaly. Here, we report the presence of PTEN mutations in two additional unrelated children with macrocephaly and autism. Our findings extend those of Butler et al. and suggest that PTEN gene sequencing should be included in the genetic evaluation of this subset of autistic individuals.

Trisomy 16p: a longitudinal profile and photo essay.

As more cases of complete or partial trisomy 16p are described, a clinical picture of these patients is emerging. A specific phenotype appears to be most consistent if the band 16p13.1-16p13.3 is present in triplicate. The hallmarks of this syndrome are microcephaly, a specific facial appearance with round facies, micrognathia, and small protruding auricles, and psychomotor as well as growth retardation. We report on a patient with partial trisomy 16p due to a maternally-inherited balanced translocation between chromosomes 2q and 16p and describe the change in phenotype over 21 years, as well as the level of development achieved.

Further delineation of Kabuki syndrome in 48 well-defined new individuals.

Kabuki syndrome is a multiple congenital anomaly/mental retardation syndrome. This study of Kabuki syndrome had two objectives. The first was to further describe the syndrome features. In order to do so, clinical geneticists were asked to submit cases-providing clinical photographs and completing a phenotype questionnaire for individuals in whom they felt the diagnosis of Kabuki syndrome was secure. All submitted cases were reviewed by four diagnosticians familiar with Kabuki syndrome. The diagnosis was agreed upon in 48 previously unpublished individuals. Our data on these 48 individuals show that Kabuki syndrome variably affects the development and function of many organ systems. The second objective of the study was to explore possible etiological clues found in our data and from review of the literature. We discuss advanced paternal age, cytogenetic abnormalities, and familial cases, and explore syndromes with potentially informative overlapping features. We find support for a genetic etiology, with a probable autosomal dominant mode of inheritance, and speculate that there is involvement of the interferon regulatory factor 6 (IRF6) gene pathway. Very recently, a microduplication of 8p has been described in multiple affected individuals, the proportion of individuals with the duplication is yet to be determined.

GTF2I hemizygosity implicated in mental retardation in Williams syndrome: genotype-phenotype analysis of five families with deletions in the Williams syndrome region.

Most individuals with Williams syndrome (WS) have a 1.6 Mb deletion in chromosome 7q11.23 that encompasses the elastin (ELN) gene, while most families with autosomal dominant supravalvar aortic stenosis (SVAS) have point mutations in ELN. The overlap of the clinical phenotypes of the two conditions (cardiovascular disease and connective tissue abnormalities such as hernias) is due to the effect of haploinsufficiency of ELN. SVAS families often have affected individuals with some WS facial features, most commonly in infancy, suggesting that ELN plays a role in WS facial gestalt as well. To find other genes contributing to the WS phenotype, we studied five families with SVAS who have small deletions in the WS region. None of the families had mental retardation, but affected family members had the Williams Syndrome Cognitive Profile (WSCP). All families shared a deletion of LIMK1, which encodes a protein strongly expressed in the brain, supporting the hypothesis that LIMK1 hemizygosity contributes to impairment in visuospatial constructive cognition. While the deletions from the families nearly spanned the WS region, none had a deletion of FKBP6 or GTF2I, suggesting that the mental retardation seen in WS is associated with deletion of either the centromeric and/or telomeric portions of the region. Comparison of these five families with reports of other individuals with partial deletions of the WS region most strongly implicates GTF2I in the mental retardation of WS.

Craniofacial-deafness-hand syndrome revisited.

In 1983 Sommer described a new syndrome in a mother and her infant daughter which was subsequently called the syndrome of craniofacial, hand anomalies and sensorineural deafness. The syndrome consisted of a normal calvarium with a flat facial profile, hypertelorism and small palpebral fissures with an antimongoloid slant, a depressed nasal bridge with a button tip and slitlike nares and a small "pursed" mouth. Profound sensorineural hearing loss and ulnar deviation of the hands with flexion contractures of digits three, four and five was evident. The family had another child, a son, two years after the birth of the index case that had the exact manifestations as his mother and sister. Because of three affected family members in two generations and a phenotype of midfacial anomalies and dystopia canthorum resembling Waardenburg syndrome, a search for mutations in the PAX3 gene was undertaken. A missense mutation in the paired domain of PAX3 (Asn47Lys) was detected. We have provided a 20-year follow-up of a syndrome characterized by craniofacial anomalies, hearing loss and hand deformities and which is caused by a PAX3 missense mutation.