Deletions of the distal short arm of chromosome 1 (1p36) represent a common, newly delineated deletion syndrome, characterized by moderate to severe psychomotor retardation, seizures, growth delay, and dysmorphic features. Previous cytogenetic underascertainment of this chromosomal deletion has made it difficult to characterize the clinical and molecular aspects of the syndrome. Recent advances in cytogenetic technology, particularly FISH, have greatly improved the ability to identify 1p36 deletions and have allowed a clearer definition of the clinical phenotype and molecular characteristics of this syndrome. We have identified 14 patients with chromosome 1p36 deletions and have assessed the frequency of each phenotypic feature and clinical manifestation in the 13 patients with pure 1p36 deletions. The physical extent and parental origin of each deletion were determined by use of FISH probes on cytogenetic preparations and by analysis of polymorphic DNA markers in the patients and their available parents. Clinical examinations revealed that the most common features and medical problems in patients with this deletion syndrome include large anterior fontanelle (100%), motor delay/hypotonia (92%), moderate to severe mental retardation (92%), growth delay (85%), pointed chin (80%), eye/vision problems (75%), seizures (72%), flat nasal bridge (65%), clinodactyly and/or short fifth finger(s) (64%), low-set ear(s) (59%), ear asymmetry (57%), hearing deficits (56%), abusive behavior (56%), thickened ear helices (53%), and deep-set eyes (50%). FISH and DNA polymorphism analysis showed that there is no uniform region of deletion but, rather, a spectrum of different deletion sizes with a common minimal region of deletion overlap.

Pseudoachondroplasia (PSACH) is a well characterized dwarfing condition mapping to chromosome 19p12-13.1. Cartilage oligomeric matrix protein (COMP), a cartilage specific protein, maps to the same location within a contig that spans the PSACH locus. Using single strand conformation polymorphism (SSCP) analysis and nucleotide sequencing we have identified COMP mutations in eight familial and isolated PSACH cases. All mutations involve either a single base-pair change or a three base-pair deletion in exon 17B. Six mutations delete or change a well conserved aspartic acid residue within the calcium-binding type 3 repeats. These results demonstrate that mutations in the COMP gene cause pseudochondroplasia.

A recessive mutation was identified in a family of transgenic mice that resulted in a reversal of left-right polarity (situs inversus) in 100 percent of the homozygous transgenic mice tested. Sequences that flanked the transgenic integration site were cloned and mapped to mouse chromosome 4, between the Tsha and Hxb loci. During early embryonic development, the direction of postimplantation turning, one of the earliest manifestations of left-right asymmetry, was reversed in homozygous transgenic embryos. This insertional mutation identifies a gene that controls embryonic turning and visceral left-right polarity.

Leber congenital amaurosis (LCA, MIM 204000) accounts for at least 5% of all inherited retinal disease and is the most severe inherited retinopathy with the earliest age of onset. Individuals affected with LCA are diagnosed at birth or in the first few months of life with severely impaired vision or blindness, nystagmus and an abnormal or flat electroretinogram (ERG). Mutations in GUCY2D (ref. 3), RPE65 (ref. 4) and CRX (ref. 5) are known to cause LCA, but one study identified disease-causing GUCY2D mutations in only 8 of 15 families whose LCA locus maps to 17p13.1 (ref. 3), suggesting another LCA locus might be located on 17p13.1. Confirming this prediction, the LCA in one Pakistani family mapped to 17p13.1, between D17S849 and D17S960-a region that excludes GUCY2D. The LCA in this family has been designated LCA4 (ref. 6). We describe here a new photoreceptor/pineal-expressed gene, AIPL1 (encoding aryl-hydrocarbon interacting protein-like 1), that maps within the LCA4 candidate region and whose protein contains three tetratricopeptide (TPR) motifs, consistent with nuclear transport or chaperone activity. A homozygous nonsense mutation at codon 278 is present in all affected members of the original LCA4 family. AIPL1 mutations may cause approximately 20% of recessive LCA, as disease-causing mutations were identified in 3 of 14 LCA families not tested previously for linkage.

The goal of this study was to expand the description of the cognitive development phenotype in boys with Klinefelter syndrome (47,XXY). We tested neuropsychological measures of memory, attention, visual-spatial abilities, visual-motor skills, and language. We examined the influence of age, handedness, genetic aspects (parental origin of the extra X chromosome, CAG(n) repeat length, and pattern of X inactivation), and previous testosterone treatment on cognition. We studied 50 boys with KS (4.1-17.8 years). There was a significant increase in left-handedness (P = 0.002). Specific language, academic, attentional, and motor abilities tended to be impaired. In the language domain, there was relative sparing of vocabulary and meaningful language understanding abilities but impairment of higher level linguistic competence. KS boys demonstrated an array of motor difficulties, especially in strength and running speed. Deficits in the ability to sustain attention without impulsivity were present in the younger boys. Neither genetic factors examined nor previous testosterone treatment accounted for variation in the cognitive phenotype in KS. The cognitive results from this large KS cohort may be related to atypical brain lateralization and have important diagnostic and psychoeducational implications. The difficulty in complex language processing, impaired attention and motor function in boys with KS may be missed. It is critical that boys with KS are provided with appropriate educational support that targets their learning challenges in school in addition to modifications that address their particular learning style. These findings would also be an important component of counseling clinicians and families about this disorder.