Familial,EsD-linked,retinoblastoma with reduced penetrance and variable expressivity

We report an example of four generation familial retinoblastoma in which there are three distinct categories of RB gene expression: frank retinoblastoma, unilateral or bilateral; retinoma; and no visible evidence of retinal pathology other than normal degeneration with age. Two large sibships derived from matings informative for RB and EsD provide strong confirmatory evidence for tight linkage between these loci (P = 0.0002), and thus assignment of RB to chromosome 13q14. There is a striking difference (P less than 2%) in RB penetrance between the two principal generations, which suggests that an additional epistatic, host-resistance gene may also be segregating within the family.     

Phenotypic characterization of Bbs4 null mice reveals age-dependent penetrance and variable expressivity

Bardet-Biedl syndrome (BBS) is a rare oligogenic disorder exhibiting both clinical and genetic heterogeneity. Although the BBS phenotype is variable both between and within families, the syndrome is characterized by the hallmarks of developmental and learning difficulties, post-axial polydactylia, obesity, hypogenitalism, renal abnormalities, retinal dystrophy, and several less frequently observed features. Eleven genes mutated in BBS patients have been identified, and more are expected to exist, since about 20–30% of all families cannot be explained by the known loci. To investigate the etiopathogenesis of BBS, we created a mouse null for one of the murine homologues, Bbs4, to assess the contribution of one gene to the pleiotropic murine Bbs phenotype. Bbs4 null mice, although initially runted compared to their littermates, ultimately become obese in a gender-dependent manner, females earlier and with more severity than males. Blood chemistry tests indicated abnormal lipid profiles, signs of liver dysfunction, and elevated insulin and leptin levels reminiscent of metabolic syndrome. As in patients with BBS, we found age-dependent retinal dystrophy. Behavioral assessment revealed that mutant mice displayed more anxiety-related responses and reduced social dominance. We noted the rare occurrence of birth defects, including neural tube defects and hydrometrocolpos, in the null mice. Evaluations of these null mice have uncovered phenotypic features with age-dependent penetrance and variable expressivity, partially recapitulating the human BBS phenotype.Electronic Supplementary Material Supplementary material is available to authorised users in the online version of this article at .     

15q11.2 microdeletion and FMR1 premutation in a family with intellectual disabilities and autism

Genomic rearrangements of chromosome 15q11–q13 are responsible for diverse phenotypes including intellectual disabilities and autism. 15q11.2 deletion, implicating common PWS/AS breakpoints BP1–BP2, has been described in patients with delayed motor and speech development and behavioural problems. Here we report the clinical and molecular characterisation of a maternally inherited BP1–BP2 deletion in two siblings with intellectual, motor and speech delay, autistic syndrome disorder and several dysmorphic features. One of the patients was also a carrier of an FMR1 allele in the low premutation range. The four genes within the deletion were under-expressed in all deletion carriers but FMR1 mRNA levels remained normal. Our results suggest that BP1-BP2 deletion could be considered as a risk factor for neuropsychological phenotypes and that it presents with variable clinical expressivity.     

Age- and gender-dependent obesity in individuals with 16p11.2 deletion

Recurrent genomic imbalances at 16p11.2 are genetic risk factors of variable penetrance for developmental delay and autism.Recently,16p11.2 (chr16:29.5 Mb-30.1 Mb) deletion has also been detected in individuals with early-onset severe obesity.The penetrance of 16p11.2deletion as a genetic risk factor for obesity is unknown.We evaluated the growth and body mass characteristics of 28 individuals with 16p11.2(chr16:29.5 Mb-30.1 Mb) deletion originally ascertained for their developmental disorders by reviewing their medical records.We found that nine individuals could be classilied as obese and six as overweight.These individuals generally had early feeding and growth difficulties,and started to gain excessive weight around 5-6 years of age.Thirteen out of the 18 deletion carriers aged 5 years and older (72％) were overweight or obese,whereas only two of 10 deletion carriers (20％) younger than five were overweight or obese.Males exhibited more severe obesity than females.Thus,the obesity phenotype of 16p11.2 deletion carriers is of juvenile onset,exhibited an age.and gender-dependent penetrance.16p11.2 deletion appears to predispose individuals to juvenile onset obesity and in this case are similar to the well-described Prader-Willi syndrome (PWS).Early detection of this deletion will provide opportunity to prevent obesity.     

2-methylbutyryl-CoA dehydrogenase deficiency associated with autism and mental retardation: a case report

Pulmonary emphysema and bronchiectasis in HIV seropositive patients has been described in the presence of injection drug use, malnutrition, repeated opportunistic infections, such as Pneumocytis jirovici pneumonia and Mycobacterium tuberculosis infection, and has been linked to the presence of HIV virus in lung tissue. Given the high burden of pulmonary infections and malnutrition among people living with HIV in resource poor settings, these individuals may be at increased risk of developing pulmonary emphysema, potentially reducing the long term benefit of antiretroviral therapy (ART) if initiated late in the course of HIV infection. In this report, we describe three HIV-infected individuals (one woman and two children) presenting with extensive pulmonary cystic disease.     

16q22.1 microdeletion detected by array-CGH in a family with mental retardation and lobular breast cancer

We describe the case of a boy with psychomotor delay and dysmorphic features, with a germline 16q22.1 microdeletion identified by array-CGH. The deletion spans 0.24Mb and encompasses three genes (ZFP90, CDH3 and CDH1). The deletion has been demonstrated to be inherited from his mother who was affected by lobular breast cancer (LBC) without any other apparently phenotypic features. We suppose that the microdeletion, in particular ZFP90 which is cerebrally expressed, is causative for the boy's phenotype. Mental retardation in the affected boy can recognize several mechanisms such as variable expressivity, non-penetrance, multifactorial/polygenic inheritance, recessive inheritance, a second rearrangement event and epigenetics. Furthermore, we suggest that the deletion of the CDH1, a tumor suppressor gene, involved in hereditary diffuse gastric cancer (HDGC) and LBC predisposed the mother to the carcinoma.     

Mental retardation and congenital malformations associated with a ring chromosome 9

Summary A 46,XY,r(9)(p24q34) complement was observed in a 35-month-old boy with multiple congenital anomalies. The main clinical features included intrauterine growth retardation, dwarfism, microcephaly, peculiar face, undescended testes, seizures and severe psychomotor retadation.It appears that 4 reported cases of r(9) can be devided into two groups. Three of them, including the present case, share clinical features with those of cases with 9p-. On the other hand, one case showed a different combination of malformations.Supported in part by a grant (No. 057364) from the Ministry of Education, Japan and a grant from the Ministry of Health and Welfare, Japan.     

Mental retardation associated with "balanced" chromosome rearrangements.

Balanced chromosome rearrangements were found in seven of 455 retarded children vs. four of 1,679 nonretarded, psychiatric children (P less than .05). The combined incidence of non-Robertsonian balanced rearrangements from this and reported surveys of the mentally retarded was five times greater than that from newborn surveys, whereas Robertsonian translocations were not increased among the retarded. The combined data show an increase in de novo rather than familial rearrangements among the retarded; the increase in de novo rearrangements is specifically for non-Robertsonian translocation.     

Variations of the candidate SEZ6L2 gene on Chromosome 16p11.2 in patients with autism spectrum disorders and in human populations

Background

Autism spectrum disorders (ASD) are a group of severe childhood neurodevelopmental disorders with still unknown etiology. One of the most frequently reported associations is the presence of recurrent de novo or inherited microdeletions and microduplications on chromosome 16p11.2. The analysis of rare variations of 8 candidate genes among the 27 genes located in this region suggested SEZ6L2 as a compelling candidate.

Methodology/Principal Findings

We further explored the role of SEZ6L2 variations by screening its coding part in a group of 452 individuals, including 170 patients with ASD and 282 individuals from different ethnic backgrounds of the Human Genome Diversity Panel (HGDP), complementing the previously reported screening. We detected 7 previously unidentified non-synonymous variations of SEZ6L2 in ASD patients. We also identified 6 non-synonymous variations present only in HGDP. When we merged our results with the previously published, no enrichment of non-synonymous variation in SEZ6L2 was observed in the ASD group compared with controls.

Conclusions/Significance

Our results provide an extensive ascertainment of the genetic variability of SEZ6L2 in human populations and do not support a major role for SEZ6L2 sequence variations in the susceptibility to ASD.     

Isolated lissencephaly sequence associated with a microdeletion at chromosome 17p13

Summary DNA markers YNZ22.1, YNH37.3, 144D6 and VAW508 were studied in a patient with the isolated lissencephaly sequence (ILS). A normal karyotype was found in the patient. The DNA of the patient showed deletions of markers YNZ22.1 and YNH37.3. This is the first report of a case of ILS (with grade 3 lissencephaly) with a submicroscopic deletion. The presence of a micro deletion in 17p13 in an ILS patient indicates that Miller-Dieker syndrome and ILS have a common etiology.     

335.4 kb microduplication in chromosome band Xp11.2p11.3 associated with developmental delay, growth retardation, autistic disorder and dysmorphic features

About 10% of causative mutations for mental retardation in male patients involve X chromosome (X-linked mental retardation, XLMR). We describe a case of a 3-year-old boy presenting with developmental delay, autistic features and growth and speech delay. Array-CGH analysis detected a microduplication on the X chromosome (Xp11.2p11.3), spanning 335.4 kb and including 3 known genes (ZNF81, ZNF182 and SPACA5). Genome-wide association studies show that approximately 30% of mutations causing XLMR are located in Xp11.2p11.3, where few pathogenic genes have been identified to date (such as ZNF41, PQB1 and ZNF81). ZNF81 codifies a zinc finger protein and mutations (non-sense mutations, deletions and structural rearrangements) involving this gene have already been described in association with mental retardation. Larger duplications in the same region have also been observed in association with mental retardation, and, in one case, the over-expression of ZNF81 has also been verified by mRNA quantification. No duplications of the single gene have been identified. To our knowledge, the microduplication found in our patient is the smallest ever described in Xp11.2p11.3. This suggests that the over-expression of ZNF81 could have pathological effects.     

Association and Mutation Analyses of 16p11.2 Autism Candidate Genes

Background

Autism is a complex childhood neurodevelopmental disorder with a strong genetic basis. Microdeletion or duplication of a ∼500–700-kb genomic rearrangement on 16p11.2 that contains 24 genes represents the second most frequent chromosomal disorder associated with autism. The role of common and rare 16p11.2 sequence variants in autism etiology is unknown.

Methodology/Principal Findings

To identify common 16p11.2 variants with a potential role in autism, we performed association studies using existing data generated from three microarray platforms: Affymetrix 5.0 (777 families), Illumina 550 K (943 families), and Affymetrix 500 K (60 families). No common variants were identified that were significantly associated with autism. To look for rare variants, we performed resequencing of coding and promoter regions for eight candidate genes selected based on their known expression patterns and functions. In total, we identified 26 novel variants in autism: 13 exonic (nine non-synonymous, three synonymous, and one untranslated region) and 13 promoter variants. We found a significant association between autism and a coding variant in the seizure-related gene SEZ6L2 (12/1106 autism vs. 3/1161 controls; p = 0.018). Sez6l2 expression in mouse embryos was restricted to the spinal cord and brain. SEZ6L2 expression in human fetal brain was highest in post-mitotic cortical layers, hippocampus, amygdala, and thalamus. Association analysis of SEZ6L2 in an independent sample set failed to replicate our initial findings.

Conclusions/Significance

We have identified sequence variation in at least one candidate gene in 16p11.2 that may represent a novel genetic risk factor for autism. However, further studies are required to substantiate these preliminary findings.     

Microduplications in 22q11.2 and 8q22.1 associated with mild mental retardation and generalized overgrowth

The 22q11.2 microduplication is a genomic disorder, characterized from a variable phenotype ranging from different defects to normality. The most common microduplication of 22q11.2 is 3 Mb in size, but there are also cases reported with atypical duplications between 0.8 Mb and 6 Mb.