Autosomal recessive mutations in THOC6 cause intellectual disability: syndrome delineation requiring forward and reverse phenotyping.

THOC6 is a part of the THO complex, which is involved in coordinating mRNA processing with export. The THO complex interacts with additional components to form the larger TREX complex (transcription export complex). Previously, a homozygous missense mutation in THOC6 in the Hutterite population was reported in association with syndromic intellectual disability. Using exome sequencing, we identified three unrelated patients with bi-allelic mutations in THOC6 associated with intellectual disability and additional clinical features. Two of the patients were compound heterozygous for a stop and a missense mutation, and the third was homozygous for a missense mutation; the missense mutations were predicted to be pathogenic by in silico analysis and modeling. Clinical features of the three newly identified patients and those previously reported are reviewed; intellectual disability is moderate to severe, and malformations are variable including renal and heart defects, cleft palate, microcephaly, and corpus callosum dysgenesis. Facial features are variable and include tall forehead, short upslanting palpebral fissures +/- deep set eyes, and a long nose with overhanging columella. These subtle facial features render the diagnosis difficult to make in isolation with certainty. Our results expand the mutational and clinical spectrum of this rare disease, confirm that THOC6 is an intellectual disability causing gene, while providing insight into the importance of the THO complex in neurodevelopment.

Non-syndromic X-linked mental retardation associated with a missense mutation (P312L) in the FGD1 gene.

Three brothers with non-syndromal X-linked mental retardation were found to have a novel missense mutation in FGD1, the gene associated with the Aarskog syndrome. Although the brothers have short stature and small feet, they lack distinct craniofacial, skeletal or genital findings suggestive of Aarskog syndrome. Their mother, the only obligate carrier available for testing, has the FGD1 mutation. The mutation, a C934T base change in exon 4, results in the proline at position 312 to be substituted with a leucine. This missense mutation is predicted to eliminate a beta-turn, creating an extra-long stretch of coiled sequence which may affect the orientations of an SH3 (Src homology 3) binding domain and the first structural conserved region. A new molecular defect associated with non-syndromal X-linked mental retardation affords an opportunity to seek specific diagnosis in males with previously unexplained developmental delays and this opens further predictive tests in families at risk.

Ritscher-Schinzel cranio-cerebello-cardiac (3C) syndrome: report of four new cases and review.

Ritscher-Schinzel syndrome, also known as the 3C syndrome, is a rare, autosomal recessive syndrome characterized by craniofacial, cerebellar, and cardiac anomalies. Cardiac manifestations include ventricular septal defect, atrial septal defect, tetralogy of Fallot, double outlet right ventricle, hypoplastic left heart, aortic stenosis, pulmonic stenosis and other valvular anomalies. Central nervous system anomalies include Dandy-Walker malformation, cerebellar vermis hypoplasia and enlargement of the cisterna magna. Craniofacial abnormalities seen are cleft palate, ocular coloboma, prominent occiput, low-set ears, hypertelorism, down-slanting palpebral fissures, depressed nasal bridge and micrognathia. Dandy-Walker malformation, posterior fossa cyst, hydrocephalus and congenital heart defect are common malformations that may occur in isolation or as a part of many syndromes. Accurate genetic diagnosis and counseling require detailed analysis of the external as well as the internal anatomy and knowledge of the relative frequencies of various malformations in syndromes that may have overlapping clinical signs. We have had the opportunity recently to study four cases of the Ritscher-Schinzel syndrome. A review of all reported cases is presented and an attempt made to define the minimum diagnostic criteria for the Ritscher-Schinzel syndrome. Of the nine craniofacial anomalies commonly reported as a part of the Ritscher-Schinzel syndrome, we consider two i.e., cleft palate and ocular coloboma, to be readily and objectively ascertainable. The other seven craniofacial traits, however, are somewhat subjective, require expert interpretation and are sometimes difficult to ascertain in a newborn or stillborn fetus. These are prominent forehead, prominent occiput, hypertelorism, down-slanting palpebral fissures, low-set ears, depressed nasal bridge and micrognathia. At least four of these were present in all cases that had a secure diagnosis of the Ritscher-Schinzel syndrome. Thus, the criteria we propose to establish the diagnosis of the Ritscher-Schinzel syndrome in a chromosomally normal sporadic case are the presence of cardiac malformation other than isolated patent ductus arteriosus, cerebellar malformation, and cleft palate or ocular coloboma or four of the following seven findings: prominent forehead, prominent occiput, hypertelorism, down-slanting palpebral fissures, low-set ears, depressed nasal bridge, and micrognathia.

Molecular characterization of breakpoints in patients with holoprosencephaly and definition of the HPE2 critical region 2p21.

Holoprosencephaly (HPE) is a common developmental defect involving the brain and face in humans. Cytogenetic deletions in patients with HPE have localized one of the HPE genes (HPE2) to the chromosomal region 2p21. Here we report the molecular genetic characterization of nine HPE patients with cytogenetic deletions or translocations involving 2p21. We have determined the parental origin of the deleted chromosomes and defined the HPE2 critical region between D2S119 and D2S88/D2S391. As a first step towards cloning the HPE2 gene which is crucial for normal brain development we have constructed a YAC contig which spans the smallest region of deletion overlap. Several of these YACs could be identified which span three different 2p21 breakpoints in HPE patients. These YACs narrow the HPE2 critical region to less than 1 Mb and are now being further analyzed to identify the gene causing holoprosencephaly on chromosome 2.

DNA testing and genetic counseling: truth or consequences.

Advances in medical genetics are providing a major clinical challenge to practitioners seeing patients concerned about their risk of developing either inherited disease or susceptibility to acquired disease. Popular information can easily exceed our professional ability to provide services to well-read patients who want answers with scientific certainty. The challenge also involves ethical questions regarding confidentiality and the way that results are disclosed. More often than not, the test itself becomes the focus of psychosocial expectations for the future and lifestyle of the patient and family. The behavioral consequences of disclosure of test results need to be anticipated by the caregiver to avoid adverse psychological outcomes.

Wisconsin consanguinity studies. II: Familial adenocarcinomatosis.

Predisposition to carcinoma in certain families has been recognized as an autosomal dominant trait. We describe a large pedigree (over 1,000 persons) including ten consanguineous unions with inbreeding coefficients from 0.02 to 0.17. Persons of consanguineous parentage accounted for 16 of 18 cases of adenocarcinoma (most of which were colorectal). Three women with breast cancer were relatives but not of consanguineous parentage. Only six of 36 persons with a malignancy of any kind were unrelated spouses, and only one of these had adenocarcinoma. Multiple primary carcinomas and/or early age-of-onset were observed only in products of consanguinity. In this extended family, the occurrence of adenocarcinoma appears to segregate as an autosomal recessive trait. It is conceivable that a proto-oncogene is segregating in this family and that, in some members, consanguineous unions have produced homozygosity for this oncogene.

Tandem dup (1p) within the short arm of chromosome 1 in a child with ambiguous genitalia and multiple congenital anomalies.

A newborn infant was found to have multiple congenital anomalies including bilateral cleft of lip and palate, intrauterine growth retardation, microcephaly, tetralogy of Fallot, ambiguous external genitalia, and presence of male and female internal genitalia. Chromosome analysis showed a tandem duplication of part of the short arm of chromosome 1, resulting in a dup(1p31----35). The karyotype designation is 46,XY,dir dup(pter----31::p35----p31::p31----qter). The exact nature of the chromosome anomaly was clarified with use of several banding methods.