Abstract Nail–patella Syndrome (NPS) is a pleiotropic disorder affecting development of the limbs, kidneys, eyes and central nervous system, which is the result of heterozygous, loss‐of‐function mutations in the transcription factor, LIM‐homeobox 1β (LMX1B). There is no correlation between the type or nature of individual mutations and the severity of the phenotype. The availability of animal models, together with analysis of gene expression patterns during development, has substantiated that the range of clinically relevant signs and symptoms is greater than appreciated previously. Evidence is building that attention deficit±hyperactivity disorder and depression may be constituent parts of the syndrome. The variation in the range and severity of symptoms, and the diverse range of affected tissues, make NPS an appropriate model in which to study the effects of gene interactions on the observed phenotype. Key Concepts: NPS is a pleiotropic, clinically variable autosomal dominant disorder. LMX1B is a member of a gene family primarily involved in regulating neuronal patterning. Loss of function mutations in LMX1B cause NPS but do not predict disease severity. Analysis of Lmx1b expression has helped explain previously unknown neural aspects of NPS. Physicians should be aware of the extra‐skeletal aspects of NPS and institute appropriate monitoring and treatment.

Nail-Patella syndrome (NPS) is an autosomal dominant disorder that is the result of heterozygous loss-of-function mutations in LMX1B, coding for a LIM homeobox (LIM-HD) transcription factor. Analyses of lmx1b mutant mice have revealed the role of Lmx1b in the development of mesencephalic dopaminergic neurons and the serotonergic system; these areas have been linked with symptoms of attention deficit hyperactivity disorder (ADHD) and major depressive disorder (MDD). Fifty adults (38 females, 12 males) with NPS completed the Conners' Adult ADHD Rating Scales-Self-report: Long Version (CAARS) and Beck Depression Inventory-II (BDI-II). The objective was to describe the neurobehavioral phenotype of these subjects and examine possible relationships between neurobehavioral symptoms and NPS. Elevated levels of DSM-IV-TR ADHD Inattentive symptoms were reported on the CAARS by 22% of the NPS sample. The BDI-II Total score was elevated for 40% of the NPS sample. There was a significant increase in the odds of an elevated BDI-II Total score when any of the three CAARS scales were elevated (odds ratios ranging from 11.455 to 15.615). The CAARS and BDI-II did not significantly differ with gender, age, or education level. There was no significant association between genetic mutation-predicted protein status and elevations on CAARS or BDI-II. Individuals with NPS reported co-occurring symptoms of ADHD and MDD, with higher levels of co-occurrence than reported in the literature for the general population. The co-occurrence of these symptoms may be related to mesencephalic dopaminergic neurologic pathway abnormalities that are a consequence of LMX1B loss of function.

Isolated cleft lip with or without cleft palate and cleft palate are among the most common human birth defects. Several candidate gene studies on MSX1 have shown significant association between markers in MSX1 and risk of oral clefts, and re-sequencing studies have identified multiple mutations in MSX1 in a small minority of cases, which may account for 1–2% of all isolated oral clefts cases. We explored the 2-Mb region around MSX1, using a marker map of 393 single nucleotide polymorphisms (SNPs) in 297 cleft lip, with or without cleft palate, case–parent trios and 84 cleft palate trios from Maryland, Taiwan, Singapore, and Korea. Both individual markers and haplotypes of two to five SNPs showed several regions yielding statistical evidence for linkage and disequilibrium. Two genes (STK32B and EVC) yielded consistent evidence from cleft lip, with or without cleft palate, trios in all four populations. These two genes plus EVC2 also yielded suggestive evidence for linkage and disequilibrium among cleft palate trios. This analysis suggests that several genes, not just MSX1, in this region may influence risk of oral clefts.

Annals of the New York Academy of SciencesVolume 785, Issue 1 p. 182-187 Hypochondroplasia: Molecular Analysis of the Fibroblast Growth Factor Receptor 3 Gene Gary A. Bellus, Gary A. Bellus Medical Genetics Branch National Center for Human Genome Research National Institutes of Health Bethesda, Maryland 20892Search for more papers by this authorIain Mcintosh, Iain Mcintosh Medical Genetics Branch National Center for Human Genome Research National Institutes of Health Bethesda, Maryland 20892Search for more papers by this authorJinny Szabo, Jinny Szabo Center for Medical Genetics Johns Hopkins University School of Medicine Baltimore, Maryland 21287Search for more papers by this authorArthur Aylsworth, Arthur Aylsworth Department of Pediatrics and the Brain Development Research Center University of North Carolina Chapel Hill North Carolina 27599Search for more papers by this authorIlkka Kaitila, Ilkka Kaitila Department of Clinical Genetics Helsinki University Hospital Helsinki, SF-00290 FinlandSearch for more papers by this authorClair A. Francomano, Corresponding Author Clair A. Francomano Medical Genetics Branch National Center for Human Genome Research National Institutes of Health Bethesda, Maryland 20892Dr. Clair Francomano, Medical Genetics Branch, National Center for Human Genome Research, National Institutes of Health, Rm. 10C-101, MSC 1852, 10 Center Drive, Bethesda, MD 20892-1852.Search for more papers by this author Gary A. Bellus, Gary A. Bellus Medical Genetics Branch National Center for Human Genome Research National Institutes of Health Bethesda, Maryland 20892Search for more papers by this authorIain Mcintosh, Iain Mcintosh Medical Genetics Branch National Center for Human Genome Research National Institutes of Health Bethesda, Maryland 20892Search for more papers by this authorJinny Szabo, Jinny Szabo Center for Medical Genetics Johns Hopkins University School of Medicine Baltimore, Maryland 21287Search for more papers by this authorArthur Aylsworth, Arthur Aylsworth Department of Pediatrics and the Brain Development Research Center University of North Carolina Chapel Hill North Carolina 27599Search for more papers by this authorIlkka Kaitila, Ilkka Kaitila Department of Clinical Genetics Helsinki University Hospital Helsinki, SF-00290 FinlandSearch for more papers by this authorClair A. Francomano, Corresponding Author Clair A. Francomano Medical Genetics Branch National Center for Human Genome Research National Institutes of Health Bethesda, Maryland 20892Dr. Clair Francomano, Medical Genetics Branch, National Center for Human Genome Research, National Institutes of Health, Rm. 10C-101, MSC 1852, 10 Center Drive, Bethesda, MD 20892-1852.Search for more papers by this author First published: June 1996 https://doi.org/10.1111/j.1749-6632.1996.tb56257.xCitations: 22AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL References 1 Walker, B. A., J. L. Murdoch, V. A. Mckusick, L. O. Langer & R. K. Beals 1971. Hypochondroplasia Amer. J. Dis. Child. 122: 95– 104. 2 Hall, B. D. & J. Spranger 1979. Hypochondroplasia: Clinical and radiological aspects in 39 cases. Radiology 133: 95– 100. 3 Wynne-Davies, R., W. K. Walsh & J. Gormley 1981. Achondroplasia and hypochondroplasia: Clinical variation and spinal stenosis. J. Bone Joint Sing. 63-B: 508– 515. 4 Maroteaux, P. & P. Falzon 1988. Hypochondroplasie: Revue di 80 cas. Arch. Fr. Pediatr. 45: 105– 109. 5 Rimoin, D. L. 1975. The chondrodystrophies. Adv. Hum. Genet 5: 13– 20. 6 Frydman, M., M. Hertz & R. M. Goodman 1974. The genetic entity of hypochondroplasia. Clin. Genet. 5: 223– 229. 7 Velinov, M., S. A. Slaugenhaupt, I. Stoilov, C. I. Scott, J. F. Gusella & P. Tsipouras 1994. The gene for achondroplasia maps to the telomeric region of chromosome 4p. Nature Genet. 3: 312– 317. 8 Lemerrer, M.F., Rousseau, L, Legeai Mallet, J. C. Landais, A. Pelet, J. Bonaventure, M. Sanak, J. Weissenbach, C. Stoll, A. Munnich & P. Maroteaux 1994. A gene for achondroplasia-hypochondroplasia maps to chromosome 4p. Nature. Genet. 6: 318– 321. 9 Francomano, C. A., R. I. Ortiz De Luna, T. W. Hefferon, G. A. Bellas, C. E. Turner, E. Taylor, D. A. Meyers, S. H. Blanton, J. C. Murray, I. Mcintosh & J. T. Hecht 1994. Localization of the achondroplasia gene to the distal 2.5 Mb of human chromosome 4p. Hum. Mol. Genet. 3: 787– 792. 10 Shiang, R., L. M. Thompson, Y.-Z. Zhu, D. M. Church, T. J. Fielder, M. Bocian, S. T. Winokur & J. J. Wasmuth 1994. Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia. Cell 78: 335– 342. 11 Rousseau, F., J. Bonaventure, L. Legeai-Mallet, A. Pelet, J.-M. Rozet, P. Maroteaux, M. Le Merrer & A. Munnich 1994. Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia. Nature 371: 252– 254. 12 Bellus, G. A., T. W. Hefferon & R. I. Ortiz De Una, J. T. Hecht, A. A. Horton, M. Machado, I. Kaitila, I. Mcintosh & C. A. Francomano 1995. Achondroplasia is defined by recurrent G380R mutations in FGFR3. Amer J. Hum. Genet. 56: 368– 373. 13 Pauli, R. M., V. K. Horton, L. P. Glinski & C. A. Reiser 1995. Prospective assessment of risks for cervicomedullary-junction compression in infants with achondroplasia. Amer J. Hum. Genet 56: 732– 744. 14 Stoilov, I., M. W. Kilpatrick & P. Tsipouras, 1995. A common FGFR3 gene mutation is present in achondroplasia but not in hypochondroplasia. Amer J. Med. Genet. 55: 127– 133. 15 Tavormina, P. L., R. Shiang, L. M. Thompson, Y.-Z. Zhu, D. J. Wilkin, R. S. Lachman, W. R. Wilcox, D. L. Rimoin & J. J. Wasmuth 1995. Mutations affecting distinct functional domains of FGFR3 cause different types of thanatophoric dysplasia. Nature Genet. 9: 321– 328. 16 Rousseau, F., P. Saugier, M. Lemerrer, A. Munnich, A. L. Delezoide, P. Maroteaux, J. Bonaventure, F. Narcy & M. Sanak 1995. Stop codon FGFR3 mutations in thanatophoric dwarfism type 1. Nature Genet 10: 11– 12. 17 Meyers, G. A., S. J. Orlow, I. R. Munro, K. A. Przylepa & E. W. Jabs 1995. Fibroblast growth factor receptor 3 (FGFR3) transmembrane mutation in Crouzon syndrome with acanthiosis nigricans. Nature Genet. 11: 462– 464. 18 Mckusick, V. A., T. E. Kelly & J. P. Dorst 1973. Observations suggesting allelism of the hypochondroplasia and achondroplasia genes. J. Med. Genet. 10: 11– 16. 19 Hecht, J. T., C. A. Ilerrera, G. A. Greenhaw, C. A. Francomano, G. A. Bellus & S. H. Blanton 1995. Confirmatory linkage of hypochondroplasia to chromosome 4p. Amer J. Med. Genet. 57: 505– 506. 20 Bellus, G. A., I. Mcintosh, E. A. Smith, A. S. Aylesworth, I. Kaitila, W. A. Horton, G. A. Greenhaw, J. T. Hecht & C. A. Francomano 1995. A recurrent mutation in the tyrosine kinase domain of fibroblast growth factor 3 causes hypochondroplasia. Nature Genet 10: 357– 359. 21 Prinos, P., T. Costa, A. Sommer, M. W. Kilpatrick & P. Tsipouras 1995. A common FGFR3 gene mutation in hypochondroplasia. Hum. Molec. Genet. 4: 2097– 2101. 22 Koeberl, D. D., C. D. K. Bottema, R. P. Ketterling, P. J. Bridge, D. P. Lillicrap & S. S. Sommer 1990. Mutations causing hemophilia B: Direct estimate of the underlying rates of spontaneous germ-line transitions, transversions and deletions in a human gene. Amer J. Hum. Genet 47: 202– 217. 23 Mullis, P. E., M. S. Patel, P. M. Brickell, P. C. Hindmarsh & C. G. D. Brook 1991. Growth characteristics and response to growth hormone therapy in patients with hypochondroplasia: Genetic linkage of the insulin-like growth factor 1 at chromosome 12q23 to the disease in a subgroup of these patients. Clin. Endocrin. 34: 265– 274. 24 Stoilov, I., M. W. Kilpatrick & P. Tsipouras & T. Costa 1995. Possible genetic heterogeneity in hypochondroplasia. J. Med. Genet. 32: 492– 493. 25 Johnson, D. E. & L. T. Williams 1993. Structural and functional diversity in the FGF receptor multigene family. Adv. Can. Res. 60: 1– 41. Citing Literature Volume785, Issue1Molecular and Developmental Biology of CartilageJune 1996Pages 182-187 ReferencesRelatedInformation

Purpose: The interferon regulatory factor 6 (IRF6), the gene that causes van der Woude syndrome has been shown to be associated with nonsyndromic cleft lip with or without palate in several populations. This study aimed to confirm the contribution of IRF6 to cleft lip with or without palate risk in additional Asian populations.Methods: A set of 13 single nucleotide polymorphisms was tested for association with cleft lip with or without palate in 77 European American, 146 Taiwanese, 34 Singaporean, and 40 Korean case-parent trios using both the transmission disequilibrium test and conditional logistic regression models.Results: Evidence of linkage and association was observed among all four populations; and two specific haplotypes [GC composed of rs2235373-rs2235371 (p.V274I) and AAG of rs599021-rs2235373-rs595918] showed the most significant over- and undertransmission among Taiwanese cases (P = 9 × 10−6 and P = 5 × 10−6, respectively). The AGC/CGC diplotype composed of rs599021-rs2235373-rs2013162 showed almost a 7-fold increase in risk among the Taiwanese sample (P < 10−3). These results confirmed the contribution of this gene to susceptibility of oral clefts across different populations; however, the specific single nucleotide polymorphisms showing statistical significance differed among ethnic groups.Conclusion: The high-risk genotypes and diplotypes identified here may provide a better understanding of the etiological role of this gene in oral clefts and potential options for genetic counseling.

We report on a 17-month-old African girl with cutaneous and ophthalmologic features of oculocutaneous albinism type 2 as well as microcephaly, absent speech, and tremulous movements. Mutations of the P gene within the Angelman/Prader-Willi syndrome critical region at 15q11-q13 cause oculocutaneous albinism type 2. Comorbid oculocutaneous albinism and Angelman syndrome were suspected and confirmed by cytogenetics. Phenotypic features of Angelman syndrome or PraderWilli syndrome in a patient with albinism should prompt further investigation. (c) 2007 by Elsevier Inc. All rights reserved.

Isolated oral clefts, including cleft lip with/without cleft palate (CL/P) and cleft palate (CP), have a complex and heterogeneous etiology. Case-parent trios from three populations were used to study genes spanning chromosome 2, where single nucleotide polymorphic (SNP) markers were analyzed individually and as haplotypes. Case-parent trios from three populations (74 from Maryland, 64 from Singapore and 95 from Taiwan) were genotyped for 962 SNPs in 104 genes on chromosome 2, including two well-recognized candidate genes: TGFA and SATB2. Individual SNPs and haplotypes (in sliding windows of 2–5 SNPs) were used to test for linkage and disequilibrium separately in CL/P and CP trios. A novel candidate gene (ZNF533) showed consistent evidence of linkage and disequilibrium in all three populations for both CL/P and CP. SNPs in key regions of ZNF533 showed considerable variability in estimated genotypic odds ratios and their significance, suggesting allelic heterogeneity. Haplotype frequencies for regions of ZNF533 were estimated and used to partition genetic variance into among-and within-population components. Wright’s fixation index, a measure of genetic diversity, showed little difference between Singapore and Taiwan compared with Maryland. The tensin-1 gene (TNS1) also showed evidence of linkage and disequilibrium among both CL/P and CP trios in all three populations, albeit at a lower level of significance. Additional genes (VAX2, GLI2, ZHFX1B on 2p; WNT6–WNT10A and COL4A3–COL4A4 on 2q) showed consistent evidence of linkage and disequilibrium only among CL/P trios in all three populations, and TGFA showed significant evidence in two of three populations.

Sir, Nail patella syndrome (NPS; OMIM #161200) is a pleiotropic condition, with a classical clinical tetrad of involvement of the nails, knees, elbows and the presence of iliac horns. Kidney disease and glaucoma are now recognized as part of the syndrome. [1] We would like to report on the spectrum of ocular manifestations in patients with nail patella syndrome that have not been reported earlier. In an observational case series study, we studied the eyes of seven patients with genetically confirmed nail patella syndrome. Examination included estimation of visual acuity, anterior segment examination using slit lamp, fundus examination with slit lamp biomicroscopy, applanation tonometry and gonioscopy. In this initial study, all our patients were noted to have anterior chamber angle abnormalities, which comprised of prominent strands of iris tissue processes attached to the trabecular meshwork, with open angles, leading us to suspect a variant of Axenfeld’s type of anomaly in patients with nail patella syndrome. Lester sign, which is a zone of darker pigmentation of cloverleaf or flower shape pattern in the central iris, was observed bilaterally in three patients. Four of the seven patients were known glaucomatous patients and were already on topical medication. The findings of our study prompt us to wonder whether the ocular features of nail patella syndrome belong to the spectrum of anterior chamber cleavage syndromes, as a variation of Axenfeld’s type of anomaly has clearly been demonstrated in the anterior chamber angle. Lester sign in the iris, though not pathognomonic, occurs more frequently in patients with NPS, as described in a study of 123 British patients. [2] Our study also highlights the increased incidence of glaucoma in patients with nail patella syndrome. This study emphasizes the need for regular screening of patients with nail patella syndrome for glaucoma. Genetic analysis of these patients showed an abnormality in the LMX1B gene on chromosome 9q34. LMX1B is also expressed in the anterior chamber of the developing eye and in the kidney throughout life, explaining the findings of glaucoma and kidney disease in NPS patients. [1] The variation in symptoms among people with NPS is not believed to be associated with the different mutations found in LMX1B but may be the result of variation in the genes with which LMX1B interacts. Further studies with a larger group of patients with nail patella syndrome are needed to prove whether the angle abnormalities as demonstrated in our study actually contribute to the development of glaucoma.

Analysis of haplotypes based on multiple single-nucleotide polymorphisms (SNP) is becoming common for both candidate gene and fine-mapping studies. Before embarking on studies of haplotypes from genetically distinct populations, however, it is important to consider variation both in linkage disequilibrium (LD) and in haplotype frequencies within and across populations, as both vary. Such diversity will influence the choice of “tagging” SNPs for candidate gene or whole-genome association studies because some markers will not be polymorphic in all samples and some haplotypes will be poorly represented or completely absent. Here we analyze 11 genes, originally chosen as candidate genes for oral clefts, where multiple markers were genotyped on individuals from four populations. Estimated haplotype frequencies, measures of pairwise LD, and genetic diversity were computed for 135 European-Americans, 57 Chinese-Singaporeans, 45 Malay-Singaporeans, and 46 Indian-Singaporeans. Patterns of pairwise LD were compared across these four populations and haplotype frequencies were used to assess genetic variation. Although these populations are fairly similar in allele frequencies and overall patterns of LD, both haplotype frequencies and genetic diversity varied significantly across populations. Such haplotype diversity has implications for designing studies of association involving samples from genetically distinct populations.

Background: Recent work suggests that multiple genes and several environmental risk factors influence risk for non-syndromic oral clefts, one of the most common birth defects in humans. Advances in high-throughput genotyping technology now make it possible to test multiple markers in many candidate genes simultaneously. Methods: We present findings from family based association tests of single nucleotide polymorphism (SNP) markers in 64 candidate genes genotyped using the BeadArray approach in 58 case-parent trios from Maryland (USA) to illustrate how multiple markers in multiple genes can be analysed. To assess whether these genes were expressed in human craniofacial structures relevant to palate and lip development, we also analysed data from the Craniofacial and Oral Gene Expression Network (COGENE) consortium, and searched public databases for expression profiles of these genes. Results: Thirteen candidate genes showed significant evidence of linkage in the presence of disequilibrium, and ten of these were found to be expressed in relevant embryonic tissues: SP100, MLPH, HDAC4, LEF1, C6orf105, CD44, ALX4, ZNF202, CRHR1, and MAPT. Three other genes showing statistical evidence (ADH1C, SCN3B, and IMP5) were not expressed in the embryonic tissues examined here. Conclusions: This approach demonstrates how statistical evidence on large numbers of SNP markers typed in case-parent trios can be combined with expression data to identify candidate genes for complex disorders. Many of the genes reported here have not been previously studied as candidates for oral clefts and warrant further investigation.

The genetic bases underlying the range and severity of phenotypes in Mendelian disorders is poorly understood; however, improvements in this area have the potential to facilitate analysis of oligogenic disorders. The nail dysplasia observed in Nail Patella Syndrome (NPS) was selected as a quantifiable variable within a Mendelian disorder, for which data could be readily obtained, to allow investigation of the genetic basis of variation. Analysis of SNP haplotypes across the LMX1B gene demonstrated association between the haplotype of the mutant allele and the variability in the nail score (p = 0.024). These results are in contrast to those obtained previously, which supported a modifying role for the wild-type allele. Since there is no evidence that particular mutations, or classes of mutation, are associated with the variation (p > 0.5), further work is required to identify the elements associated with the LMX1B gene that mediate phenotypic severity.