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1.  Clinical spectrum of SIX3-associated mutations in holoprosencephaly: correlation between genotype, phenotype and function 
Journal of medical genetics  2009;46(6):389-398.
Background
Holoprosencephaly (HPE) is the most common structural malformation of the human forebrain. There are several important HPE mutational target genes, including the transcription factor SIX3, which encodes an early regulator of Shh, Wnt, Bmp and Nodal signalling expressed in the developing forebrain and eyes of all vertebrates.
Objective
To characterise genetic and clinical findings in patients with SIX3 mutations.
Methods
Patients with HPE and their family members were tested for mutations in HPE-associated genes and the genetic and clinical findings, including those for additional cases found in the literature, were analysed. The results were correlated with a mutation-specific functional assay in zebrafish.
Results
In a cohort of patients (n = 800) with HPE, SIX3 mutations were found in 4.7% of probands and additional cases were found through testing of relatives. In total, 138 cases of HPE were identified, 59 of whom had not previously been clinically presented. Mutations in SIX3 result in more severe HPE than in other cases of non-chromosomal, non-syndromic HPE. An over-representation of severe HPE was found in patients whose mutations confer greater loss of function, as measured by the functional zebrafish assay. The gender ratio in this combined set of patients was 1.5:1 (F:M) and maternal inheritance was almost twice as common as paternal. About 14% of SIX3 mutations in probands occur de novo. There is a wide intrafamilial clinical range of features and classical penetrance is estimated to be at least 62%.
Conclusions
Our data suggest that SIX3 mutations result in relatively severe HPE and that there is a genotype–phenotype correlation, as shown by functional studies using animal models.
doi:10.1136/jmg.2008.063818
PMCID: PMC3510661  PMID: 19346217
2.  Further delineation of the 15q13 microdeletion and duplication syndromes: A clinical spectrum varying from non-pathogenic to a severe outcome 
Journal of Medical Genetics  2009;46(8):511-523.
Background
Recurrent 15q13.3 microdeletions were recently identified with identical proximal (BP4) and distal (BP5) breakpoints and associated with mild to moderate mental retardation and epilepsy.
Methods
To further assess the clinical implications of this novel 15q13.3 microdeletion syndrome, eighteen new probands with a deletion were molecularly and clinically characterised. In addition, we evaluated the characteristics of a family with a more proximal deletion between BP3 and BP4. Finally, four patients with a duplication in the BP3-BP4-BP5 region were included in this study to ascertain the clinical significance of duplications in this region.
Results
The 15q13.3 microdeletion in our series was associated with a highly variable intra- and inter-familial phenotype. At least 11 of the 18 deletions identified were inherited. Moreover, 7 of 10 siblings from four different families also had this deletion: one had a mild developmental delay, four had only learning problems during childhood, but functioned well in daily life as adults, whereas the other two had no learning problems at all. In contrast to previous findings, seizures were not a common feature in our series (only 2 of 17 living probands). Three patients with deletions had cardiac defects and deletion of the KLF13 gene, located in the critical region, may contribute to these abnormalities. The limited data from the single family with the more proximal BP3-BP4 deletion suggest this deletion may have little clinical significance. Patients with duplications of the BP3-BP4-BP5 region did not share a recognizable phenotype, but psychiatric disease was noted in 2 of 4 patients.
Conclusions
Overall, our findings broaden the phenotypic spectrum associated with 15q13.3 deletions and suggest that, in some individuals, deletion of 15q13.3 is not sufficient to cause disease. The existence of microdeletion syndromes, associated with an unpredictable and variable phenotypic outcome, will pose the clinician with diagnostic difficulties and challenge the commonly used paradigm in the diagnostic setting that aberrations inherited from a phenotypically normal parent are usually without clinical consequences.
doi:10.1136/jmg.2008.063412
PMCID: PMC3395372  PMID: 19372089
15q13.3; KLF13; CHRNA7; epilepsy; cardiac
3.  A 380-kb Duplication in 7p22.3 Encompassing the LFNG Gene in a Boy with Asperger Syndrome 
Molecular Syndromology  2012;2(6):245-250.
De novo genomic aberrations are considered an important cause of autism spectrum disorders. We describe a de novo 380-kb gain in band p22.3 of chromosome 7 in a patient with Asperger syndrome. This duplicated region contains 9 genes including the LNFG gene that is an important regulator of NOTCH signaling. We suggest that this copy number variation has been a contributive factor to the occurrence of Asperger syndrome in this patient.
doi:10.1159/000336191
PMCID: PMC3362183  PMID: 22822384
Autism spectrum disorder; Chromosome 7p22.3; Duplication; Gain; Lunatic fringe
4.  Psychological distress in newly diagnosed colorectal cancer patients following microsatellite instability testing for Lynch syndrome on the pathologist’s initiative 
Familial Cancer  2012;11(2):259-267.
According to the Dutch Guideline on Hereditary Colorectal Cancer published in 2008, patients with recently diagnosed colorectal cancer (CRC) should undergo microsatellite instability (MSI) testing by a pathologist immediately after tumour resection if they are younger than 50 years, or if a second CRC has been diagnosed before the age of 70 years, owing to the high risk of Lynch syndrome (MIPA). The aim of the present MIPAPS study was to investigate general distress and cancer-specific distress following MSI testing. From March 2007 to September 2009, 400 patients who had been tested for MSI after newly diagnosed CRC were recruited from 30 Dutch hospitals. Levels of general distress (SCL-90) and cancer-specific distress (IES) were assessed immediately after MSI result disclosure (T1) and 6 months later (T2). Response rates were 23/77 (30%) in the MSI-positive patients and 58/323 (18%) in the MSI-negative patients. Levels of general distress and cancer-specific distress were moderate. In the MSI-positive group, 27% of the patients had high general distress at T1 versus 18% at T2 (p = 0.5), whereas in the MSI-negative group, these percentage were 14 and 18% (p = 0.6), respectively. At T1 and T2, cancer-specific distress rates in the MSI-positive group and MSI-negative group were 39 versus 27% (p = 0.3) and 38 versus 36% (p = 1.0), respectively. High levels of general distress were correlated with female gender, low social support and high perceived cancer risk. Moderate levels of distress were observed after MSI testing, similar to those found in other patients diagnosed with CRC. Immediately after result disclosure, high cancer-specific distress was observed in 40% of the MSI-positive patients.
doi:10.1007/s10689-012-9510-1
PMCID: PMC3365237  PMID: 22311584
Colorectal cancer; Genetic testing; Hereditary cancer; Microsatellite instability testing; Psychological distress
5.  Clinical and molecular delineation of the 17q21.31 microdeletion syndrome 
Journal of medical genetics  2008;45(11):710-720.
Background
The chromosome 17q21.31 microdeletion syndrome is a novel genomic disorder that has originally been identified using high resolution genome analyses in patients with unexplained mental retardation.
Aim
We report the molecular and/or clinical characterisation of 22 individuals with the 17q21.31 microdeletion syndrome.
Results
We estimate the prevalence of the syndrome to be 1 in 16 000 and show that it is highly underdiagnosed. Extensive clinical examination reveals that developmental delay, hypotonia, facial dysmorphisms including a long face, a tubular or pear-shaped nose and a bulbous nasal tip, and a friendly/amiable behaviour are the most characteristic features. Other clinically important features include epilepsy, heart defects and kidney/urologic anomalies. Using high resolution oligonucleotide arrays we narrow the 17q21.31 critical region to a 424 kb genomic segment (chr17: 41046729–41470954, hg17) encompassing at least six genes, among which is the gene encoding microtubule associated protein tau (MAPT). Mutation screening of MAPT in 122 individuals with a phenotype suggestive of 17q21.31 deletion carriers, but who do not carry the recurrent deletion, failed to identify any disease associated variants. In five deletion carriers we identify a <500 bp rearrangement hotspot at the proximal breakpoint contained within an L2 LINE motif and show that in every case examined the parent originating the deletion carries a common 900 kb 17q21.31 inversion polymorphism, indicating that this inversion is a necessary factor for deletion to occur (p<10–5).
Conclusion
Our data establish the 17q21.31 microdeletion syndrome as a clinically and molecularly well recognisable genomic disorder.
doi:10.1136/jmg.2008.058701
PMCID: PMC3071570  PMID: 18628315
6.  Predicting disease genes using protein–protein interactions 
Journal of Medical Genetics  2006;43(8):691-698.
Background
The responsible genes have not yet been identified for many genetically mapped disease loci. Physically interacting proteins tend to be involved in the same cellular process, and mutations in their genes may lead to similar disease phenotypes.
Objective
To investigate whether protein–protein interactions can predict genes for genetically heterogeneous diseases.
Methods
72 940 protein–protein interactions between 10 894 human proteins were used to search 432 loci for candidate disease genes representing 383 genetically heterogeneous hereditary diseases. For each disease, the protein interaction partners of its known causative genes were compared with the disease associated loci lacking identified causative genes. Interaction partners located within such loci were considered candidate disease gene predictions. Prediction accuracy was tested using a benchmark set of known disease genes.
Results
Almost 300 candidate disease gene predictions were made. Some of these have since been confirmed. On average, 10% or more are expected to be genuine disease genes, representing a 10‐fold enrichment compared with positional information only. Examples of interesting candidates are AKAP6 for arrythmogenic right ventricular dysplasia 3 and SYN3 for familial partial epilepsy with variable foci.
Conclusions
Exploiting protein–protein interactions can greatly increase the likelihood of finding positional candidate disease genes. When applied on a large scale they can lead to novel candidate gene predictions.
doi:10.1136/jmg.2006.041376
PMCID: PMC2564594  PMID: 16611749
disease gene; candidate gene; disease gene prediction; protein–protein interactions; bioinformatics
7.  A second locus for Aicardi‐Goutières syndrome at chromosome 13q14–21 
Journal of Medical Genetics  2005;43(5):444-450.
Background
Aicardi‐Goutières syndrome (AGS) is an autosomal recessive, early onset encephalopathy characterised by calcification of the basal ganglia, chronic cerebrospinal fluid lymphocytosis, and negative serological investigations for common prenatal infections. AGS may result from a perturbation of interferon α metabolism. The disorder is genetically heterogeneous with approximately 50% of families mapping to the first known locus at 3p21 (AGS1).
Methods
A genome‐wide scan was performed in 10 families with a clinical diagnosis of AGS in whom linkage to AGS1 had been excluded. Higher density genotyping in regions of interest was also undertaken using the 10 mapping pedigrees and seven additional AGS families.
Results
Our results demonstrate significant linkage to a second AGS locus (AGS2) at chromosome 13q14–21 with a maximum multipoint heterogeneity logarithm of the odds (LOD) score of 5.75 at D13S768. The AGS2 locus lies within a 4.7 cM region as defined by a 1 LOD‐unit support interval.
Conclusions
We have identified a second AGS disease locus and at least one further locus. As in a number of other conditions, genetic heterogeneity represents a significant obstacle to gene identification in AGS. The localisation of AGS2 represents an important step in this process.
doi:10.1136/jmg.2005.031880
PMCID: PMC2649012  PMID: 15908569
AGS2; Aicardi‐Goutières syndrome; interferon α; intracranial calcification; 13q14–21
8.  CHARGE syndrome: the phenotypic spectrum of mutations in the CHD7 gene 
Journal of Medical Genetics  2005;43(4):306-314.
Background
CHARGE syndrome is a non‐random clustering of congenital anomalies including coloboma, heart defects, choanal atresia, retarded growth and development, genital hypoplasia, ear anomalies, and deafness. A consistent feature in CHARGE syndrome is semicircular canal hypoplasia resulting in vestibular areflexia. Other commonly associated congenital anomalies are facial nerve palsy, cleft lip/palate, and tracheo‐oesophageal fistula. Specific behavioural problems, including autistic‐like behaviour, have been described. The CHD7 gene on chromosome 8q12.1 was recently discovered as a major gene involved in the aetiology of this syndrome.
Methods
The coding regions of CHD7 were screened for mutations in 107 index patients with clinical features suggestive of CHARGE syndrome. Clinical data of the mutation positive patients were sampled to study the phenotypic spectrum of mutations in the CHD7 gene.
Results
Mutations were identified in 69 patients. Here we describe the clinical features of 47 of these patients, including two sib pairs. Most mutations were unique and were scattered throughout the gene. All patients but one fulfilled the current diagnostic criteria for CHARGE syndrome. No genotype‐phenotype correlations were apparent in this cohort, which is best demonstrated by the differences in clinical presentation in sib pairs with identical mutations. Somatic mosaicism was detected in the unaffected mother of a sib pair, supporting the existence of germline mosaicism.
Conclusions
CHD7 mutations account for the majority of the cases with CHARGE syndrome, with a broad clinical variability and without an obvious genotype‐phenotype correlation. In one case evidence for germline mosaicism was provided.
doi:10.1136/jmg.2005.036061
PMCID: PMC2563221  PMID: 16155193
CHARGE syndrome;  CHD7 ; clinical spectrum
9.  Shortened time interval between colorectal cancer diagnosis and risk testing for hereditary colorectal cancer is not related to higher psychological distress 
Familial Cancer  2010;10(1):51-57.
Current diagnostic practices have shortened the interval between colorectal cancer (CRC) diagnosis and genetic analysis for Lynch syndrome by MSI-testing. We studied the relation of time between MSI-testing since CRC diagnosis (MSI–CRC interval) and psychological distress. We performed a cross-sectional study in 89 patients who had previously been treated for CRC. Data were collected during MSI-testing after genetic counseling. Psychological distress was measured with the IES, the SCL-90 and the POMS; social issues with the ISS, ISB and the ODHCF. The median time of MSI–CRC interval was 24 months (range 0–332), with 23% of the patients diagnosed less than 12 months and 42% more than 36 months prior to MSI-testing. In 34% of the patients cancer specific distress was high (IES scores >26). Mean psychopathology (SCL-90) scores were low, mean mood states (POMS) scores were moderate. Interval MSI–CRC was not related to psychological distress. High cancer specific distress was reported by 24% of patients diagnosed with CRC less than 12 months ago versus 39 and 35% by those diagnosed between 12 and 36 months and more than 36 months ago respectively. Distress was positively related to female gender (P = 0.04), religiousness (P = 0.01), low social support (P = 0.02) and difficulties with family communication (P < 0.001). Shortened time interval between CRC diagnosis and MSI-testing is not associated with higher psychological distress. Females, religious persons, those having low social support and those reporting difficulties communicating hereditary colorectal cancer with relatives are at higher risk for psychological distress.
doi:10.1007/s10689-010-9387-9
PMCID: PMC3036824  PMID: 20853153
Colorectal cancer; Genetic testing; Lynch syndrome; MSI-analysis; Psychological distress; Time
10.  Severe Progressive Autism Associated with Two de novo Changes: A 2.6-Mb 2q31.1 Deletion and a Balanced t(14;21)(q21.1;p11.2) Translocation with Long-Range Epigenetic Silencing of LRFN5 Expression 
Molecular Syndromology  2010;1(1):46-57.
In a 19-year-old severely autistic and mentally retarded girl, a balanced de novo t(14;21)(q21.1;p11.2) translocation was found in addition to a de novo 2.6-Mb 2q31.1 deletion containing 15 protein-encoding genes. To investigate if the translocation might contribute to developmental stagnation at the age of 2 years with later regression of skills, i.e. a more severe phenotype than expected from the 2q31.1 deletion, the epigenetic status and expression of genes proximal and distal to the 14q21.1 breakpoint were investigated in Ebstein Barr Virus-transformed lymphoblast and primary skin fibroblast cells. The 14q21.1 breakpoint was found to be located between a cluster of 7 genes 0.1 Mb upstream, starting with FBXO33, and the single and isolated LRFN5 gene 2.1 Mb downstream. Only expression of LRFN5 appeared to be affected by its novel genomic context. In patient fibroblasts, LRFN5 expression was 10-fold reduced compared to LRFN5 expressed in control fibroblasts. In addition, a relative increase in trimethylated histone H3 lysine 9 (H3K9M3)-associated DNA starting exactly at the translocation breakpoint and going 2.5 Mb beyond the LRFN5 gene was found. At the LRFN5 promoter, there was a distinct peak of trimethylated histone H3 lysine 27 (H3K27M3)-associated DNA in addition to a diminished trimethylated histone H3 lysine 4 (H3K4M3) level. We speculate that dysregulation of LRFN5, a postsynaptic density-associated gene, may contribute to the patient's autism, even though 2 other patients with 14q13.2q21.3 deletions that included LRFN5 were not autistic. More significantly, we have shown that translocations may influence gene expression more than 2 Mb away from the translocation breakpoint.
doi:10.1159/000280290
PMCID: PMC2883852  PMID: 20648246
Deletion 2q31.1; Epigenetics; Gene silencing; LRFN5; Translocation
11.  Patients with an unexplained microsatellite instable tumour have a low risk of familial cancer 
British Journal of Cancer  2007;96(10):1605-1612.
The cancer risk is unknown for those families in which a microsatellite instable tumour is neither explained by MLH1 promoter methylation nor by a germline mutation in a mismatch repair (MMR) gene. Such information is essential for genetic counselling. Families suspected of Lynch syndrome (n=614) were analysed for microsatellite instability, MLH1 promoter methylation and/or germline mutations in MLH1, MSH2, MSH6, and PMS2. Characteristics of the 76 families with a germline mutation (24 MLH1, 2 PMS2, 32 MSH2, and 18 MSH6) were compared with those of 18 families with an unexplained microsatellite instable tumour. The mean age at diagnosis of the index patients in both groups was comparable at 44 years. Immunohistochemistry confirmed the loss of an MMR protein. Together this suggests germline inactivation of a known gene. The Amsterdam II criteria were fulfilled in 50/75 families (66%) that carried a germline mutation in an MMR gene and in only 2/18 families (11%) with an unexplained microsatellite instable tumour (P<0.0001). Current diagnostic strategies can detect almost all highly penetrant MMR gene mutations. Patients with an as yet unexplained microsatellite instable tumour likely carry a different type of mutation that confers a lower risk of cancer for relatives.
doi:10.1038/sj.bjc.6603754
PMCID: PMC2359954  PMID: 17453009
colorectal neoplasms; hereditary nonpolyposis; microsatellite instability; DNA mismatch repair; DNA methylation
12.  Very low prevalence of germline MSH6 mutations in hereditary non-polyposis colorectal cancer suspected patients with colorectal cancer without microsatellite instability 
British Journal of Cancer  2006;95(12):1678-1682.
Hereditary non-polyposis colorectal cancer (HNPCC) is caused by mutations in one of the mismatch repair genes MLH1, MSH2, MSH6, or PMS2 and results in high-level microsatellite instability (MSI-high) in tumours of HNPCC patients. The MSI test is considered reliable for indicating mutations in MLH1 and MSH2, but is questioned for MSH6. Germline mutation analysis was performed in 19 patients with an MSI-high tumour and absence of MSH2 and/or MSH6 protein as determined by immunohistochemistry (IHC), without an MLH1 or MSH2 mutation, and in 76 out of 295 patients suspected of HNPCC, with a non-MSI-high colorectal cancer (CRC). All 295 non-MSI-high CRCs were analysed for presence of MSH6 protein by IHC. In 10 patients with an MSI-high tumour without MSH2 and/or MSH6 expression, a pathogenic MSH6 mutation was detected, whereas no pathogenic MSH6 mutation was detected in 76 patients with a non-MSI-high CRC and normal MSH6 protein expression. In none of the 295 CRCs loss of MSH6 protein expression was detected. The prevalence of a germline MSH6 mutation is very low in HNPCC suspected patients with non-MSI-high CRC. Microsatellite instability analysis in CRCs is highly sensitive to select patients for MSH6 germline mutation analysis.
doi:10.1038/sj.bjc.6603478
PMCID: PMC2360757  PMID: 17117178
MSI; HNPCC; hereditary cancer; MSH6
13.  The prevalence of PAX2 mutations in patients with isolated colobomas or colobomas associated with urogenital anomalies. 
Journal of Medical Genetics  1998;35(10):806-812.
The PAX2 gene is mutated in patients with ocular colobomas, vesicoureteral reflux (VUR), and kidney anomalies (renal-coloboma syndrome, OMIM 120330). The three abnormalities which make up this syndrome also occur in isolation, but the causal genes are not known. PAX2 encodes a transcription factor of the paired box class of DNA binding proteins, important for the development of the urogenital tract, optic nerve and adjacent retina, inner ear, and CNS. In this paper we have investigated the prevalence of PAX2 mutations in patients with ocular colobomas, microphthalmos, or retinal anomalies, either in isolation or with associated urogenital anomalies. Using PCR-SSCP, most or all exons of PAX2 were examined in blood DNA from 99 patients who have either ocular anomalies alone or a combination of ocular and urogenital conditions. PAX2 mutations were not detected in patients with ocular colobomas, either in isolation or with associated abnormalities, except in one patient with typical renal-coloboma syndrome. We conclude that PAX2 mutations are unlikely to be common in patients with ocular colobomas in isolation or in patients with ocular colobomas and associated anomalies, except for patients with typical renal-coloboma syndrome where PAX2 is known to be the aetiological cause.
Images
PMCID: PMC1051454  PMID: 9783702
14.  Anticipation resulting in elimination of the myotonic dystrophy gene: a follow up study of one extended family. 
Journal of Medical Genetics  1994;31(8):595-601.
We have re-examined an extended myotonic dystrophy (DM) family, previously described in 1955, in order to study the long term effects of anticipation in DM and in particular the implications for families affected by this disease. This follow up study provides data on 35 gene carriers and 46 asymptomatic at risk family members in five generations. Clinical anticipation, defined as the cascade of mild, adult, childhood, or congenital disease in subsequent generations, appeared to be a relentless process, occurring in all affected branches of the family. The cascade was found to proceed asynchronously in the different branches, mainly because of an unequal number of generations with mild disease. The transition from the mild to the adult type was associated with transmission through a male parent. Stable transmission of the asymptomatic/mild phenotype showed a female transmission bias. We further examined the extent and causes of gene loss in this pedigree. Gene loss in the patient group was complete, owing to infertility of the male patients with adult onset disease and the fact that mentally retarded patients did not procreate. Out of the 46 at risk subjects in the two youngest generations, only one was found to have a full mutation. This is the only subject who may transmit the gene to the sixth generation. No protomutation carriers were found in the fourth and fifth generations. Therefore it is highly probable that the DM gene will be eliminated from this pedigree within one generation. The high population frequency of DM can at present not be explained by the contribution of asymptomatic cases in the younger generations of known families, but is probably caused by the events in the ancestral generations.
PMCID: PMC1050019  PMID: 7815415
15.  Linkage analysis with chromosome 15q11-13 markers shows genomic imprinting in familial Angelman syndrome. 
Journal of Medical Genetics  1992;29(12):853-857.
Angelman syndrome (AS) and Prader-Willi syndrome (PWS) have become the classical examples of genomic imprinting in man, as completely different phenotypes are generated by the absence of maternal (AS) or paternal (PWS) contributions to the q11-13 region of chromosome 15 as a result of deletion or uniparental disomy. Apparently, most patients are sporadic cases. The genetic mechanism underlying familial AS has remained enigmatic for a long time. Recently, evidence has been emerging suggesting autosomal dominant inheritance of a detectable or undetectable defect in a gene or genes at 15q11-13, subject to genomic imprinting. The present report describes an unusually large pedigree with segregation of AS through maternal inheritance and apparent asymptomatic transmission through several male ancestors. Deletion and paternal disomy at 15q11-13 were excluded. However, the genetic defect is still located in this region, as we obtained a maximum lod score of 5.40 for linkage to the GABA receptor locus GABRB3 and the anonymous DNA marker D15S10, which have been mapped within or adjacent to the AS critical region at 15q11-13. The size of the pedigree allowed calculation of an odds ratio in favour of genomic imprinting of 9.25 x 10(5). This family illustrates the necessity of extensive pedigree analysis when considering recurrence risks for relatives of AS patients, those without detectable deletion or disomy in particular.
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PMCID: PMC1016200  PMID: 1362220
16.  GeneSeeker: extraction and integration of human disease-related information from web-based genetic databases 
Nucleic Acids Research  2005;33(Web Server issue):W758-W761.
The identification of genes underlying human genetic disorders requires the combination of data related to cytogenetic localization, phenotypes and expression patterns, to generate a list of candidate genes. In the field of human genetics, it is normal to perform this combination analysis by hand. We report on GeneSeeker (), a web server that gathers and combines data from a series of databases. All database searches are performed via the web interfaces provided with the original databases, guaranteeing that the most recent data are queried, and obviating data warehousing. GeneSeeker makes the same selection of candidate genes as the human geneticists would have performed, and thus reducing the time-consuming process to a few minutes. GeneSeeker is particularly well suited for syndromes in which the disease gene displays altered expression patterns in the affected tissue(s).
doi:10.1093/nar/gki435
PMCID: PMC1160196  PMID: 15980578
17.  Benign familial hematuria due to mutation of the type IV collagen alpha4 gene. 
Journal of Clinical Investigation  1996;98(5):1114-1118.
Benign familial hematuria (BFH) is characterized by autosomal dominant inheritance, thinning of the glomerular basement membrane (GBM) and normal renal function. It is frequent in patients with persistent microscopic hematuria, but cannot be clinically differentiated from the initial stages of Alport syndrome, a severe GBM disorder which progresses to renal failure. We present here linkage of benign familial hematuria with the COL4A3 and COL4A4 genes at 2q35-37 (Zmax = 3.58 at theta = 0.0). Subsequently, a glycine to glutamic acid substitution was identified in the collagenous region of the COL4A4 gene. We conclude that type IV collagen defects cause both benign hematuria and Alport syndrome. Furthermore, our data suggest that BFH patients can be carriers of autosomal recessive Alport syndrome.
PMCID: PMC507532  PMID: 8787673
18.  Specific genetic deficiencies of the A and B isoenzymes of monoamine oxidase are characterized by distinct neurochemical and clinical phenotypes. 
Journal of Clinical Investigation  1996;97(4):1010-1019.
Monoamine oxidase (MAO) exists as two isoenzymes and plays a central role in the metabolism of monoamine neurotransmitters. In this study we compared the neurochemical phenotypes of previously described subjects with genetically determined selective lack of MAO-A or a lack of both MAO-A and MAO-B with those of two subjects with a previously described X chromosome microdeletion in whom we now demonstrate selective MAO-B deficiency. Mapping of the distal deletion breakpoint demonstrates its location in intron 5 of the MAO-B gene, with the deletion extending proximally into the Norrie disease gene. In contrast to the borderline mental retardation and abnormal behavioral phenotype in subjects with selective MAO-A deficiency and the severe mental retardation in patients with combined MAO-A/MAO-B deficiency and Norrie disease, the MAO-B-deficient subjects exhibit neither abnormal behavior nor mental retardation. Distinct neurochemical profiles characterize the three groups of MAO-deficient patients. In MAO-A-deficient subjects, there is a marked decrease in deaminated catecholamine metabolites and a concomitant marked elevation of O-methylated amine metabolites. These neurochemical changes are only slightly exaggerated in patients with combined lack of MAO-A and MAO-B. In contrast, the only biochemical abnormalities detected in subjects with the MAO-B gene deletion are a complete absence of platelet MAO-B activity and an increased urinary excretion of phenylethylamine. The differences in neurochemical profiles indicate that, under normal conditions, MAO-A is considerably more important than MAO-B in the metabolism of biogenic amines, a factor likely to contribute to the different clinical phenotypes.
PMCID: PMC507147  PMID: 8613523
19.  Intestinal pseudo-obstruction in myotonic dystrophy. 
Journal of Medical Genetics  1992;29(11):791-793.
We describe four myotonic dystrophy (DM) patients who developed recurrent intestinal pseudo-obstruction. Some episodes were associated with gastroenteritis, while abdominal crowding may have occurred in one case during the third trimester of pregnancy. In most instances, however, no apparent cause could be identified. Intestinal pseudo-obstruction may occur at any stage of DM. In one of our cases intestinal pseudo-obstruction preceded significant muscle weakness by 15 years. Intestinal pseudo-obstruction is usually treated effectively with conservative measures. These include restriction of oral intake, intravenous fluids, and multiple enemas or colonoscopy. Improved intestinal function was noted in one case treated with the prokinetic agent cisapride. A partial sigmoid resection was performed in three cases with dolichomegacolon. No abnormalities were reported on histological examination. Since intestinal pseudo-obstruction is a rare complication of DM, it is of interest that two of our cases are sibs. Review of published reports showed several reports of familial occurrence of specific complications. These include cardiac conduction disturbances, focal myocarditis, mitral valve prolapse, pilomatrixomas, polyneuropathy, normal pressure hydrocephalus, and dilatation of the urinary tract. Myotonic dystrophy may show a tendency to familial clustering of organ specific involvement.
PMCID: PMC1016174  PMID: 1453429
20.  Presymptomatic diagnosis of myotonic dystrophy. 
Journal of Medical Genetics  1992;29(11):780-784.
The discovery of an expanded (CTG)n repeat sequence in myotonic dystrophy (DM) has greatly improved our ability to detect DM gene carriers who have few or none of the classical signs of this disorder. We report here our experience with two such groups of gene carriers. We used a PCR based protocol that should be especially sensitive to small increases in CTG triplet number which might escape detection by conventional Southern blot analysis. Our analyses show that on 100 non-DM chromosomes the number of CTG triplets ranged from five to 37. We then studied 17 obligate gene carriers aged 55 years and over who showed no muscle weakness. All of the gene carriers in this group showed a relatively small increase in the number of CTG triplets (52 to 90 CTG triplets) with limited somatic mosaicism. We subsequently studied 11 subjects (aged 19 to 36 years) who had previously been identified as gene carriers by genetic linkage studies, but who lacked diagnostic signs. In this prospectively studied group, nine subjects showed an expanded allele, confirming the earlier prediction from linked genetic markers. The other two subjects had only two normal alleles and no expanded allele. Revision of the clinical data casts doubt on the original diagnosis of DM in their families. Preferential amplification of the normal non-expanded allele was noted in three asymptomatic gene carriers in this study (as well as in two of their clinically affected relatives). We caution that, at least in our hands, the DM mutation can be confidently excluded by this PCR based method only if both normal alleles have been identified.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMCID: PMC1016170  PMID: 1453426
21.  Autosomal dominant inheritance of abnormalities of the hands and feet with short palpebral fissures, variable microcephaly with learning disability, and oesophageal/duodenal atresia. 
Journal of Medical Genetics  1991;28(6):389-394.
We report two families with an autosomal dominant syndrome of abnormalities of the hands and feet, short palpebral fissures, and variable microcephaly with learning disability. Between a third and a quarter of cases are born with oesophageal atresia, duodenal atresia, or both. Individual patients have hypoplastic thumbs or congenital heart disease. The phenotype of the syndrome reported here is similar to that observed in 13q22-qter deletion patients. However, chromosome analysis has not detected any structural abnormality in our patients.
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PMCID: PMC1016903  PMID: 1870095

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