Fumarase deficiency (FD) is a rare and severe autosomal disorder, caused by inactivity of the enzyme fumarase, due to biallelic mutations of the fumarase hydratase (FH) gene. Several pathogenic mutations have been published. The article describes an infant with failure to thrive, microcephaly, axial hypotonia, and developmental retardation with increased excretion of fumarate, no activity of fumarase and a homozygous mutation of the FH gene, which was until recently only known as a variant of unknown significance. Carriers of pathogenic mutations in the FH gene are at risk for developing renal cell carcinoma and should therefore be screened. Both parents were healthy carriers of the mutation and had decreased levels of enzyme activity. In addition, the article presents an overview and analysis of all cases of FD reported thus far in the literature.

Aminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed enzymes implicated in several dominant and recessive disease phenotypes. The canonical function of ARSs is to couple an amino acid to a cognate transfer RNA (tRNA). We identified three novel disease-associated missense mutations in the alanyl-tRNA synthetase (AARS) gene in three families with dominant axonal Charcot-Marie-Tooth (CMT) disease. Two mutations (p.Arg326Trp and p.Glu337Lys) are located near a recurrent pathologic change in AARS, p.Arg329His. The third (p.Ser627Leu) is in the editing domain of the protein in which hitherto only mutations associated with recessive encephalopathies have been described. Yeast complementation assays demonstrated that two mutations (p.Ser627Leu and p.Arg326Trp) represent loss-of-function alleles, while the third (p.Glu337Lys) represents a hypermorphic allele. Further, aminoacylation assays confirmed that the third mutation (p.Glu337Lys) increases tRNA charging velocity. To test the effect of each mutation in the context of a vertebrate nervous system, we developed a zebrafish assay. Remarkably, all three mutations caused a pathological phenotype of neural abnormalities when expressed in zebrafish, while expression of the human wild-type messenger RNA (mRNA) did not. Our data indicate that not only functional null or hypomorphic alleles, but also hypermorphic AARS alleles can cause dominantly inherited axonal CMT disease.

PURPOSE:To identify the genetic cause of and describe the phenotype in 4 families with autosomal recessive retinitis pigmentosa (arRP) that can be associated with pseudocoloboma. DESIGN:Case series. PARTICIPANTS:Seven patients from 4 unrelated families with arRP, among whom 3 patients had bilateral early-onset macular pseudocoloboma. METHODS:We performed homozygosity mapping and whole-exome sequencing in 5 probands and 2 unaffected family members from 4 unrelated families. Subsequently, Sanger sequencing and segregation analysis were performed in additional family members. We reviewed the medical history of individuals carrying IDH3A variants and performed additional ophthalmic examinations, including full-field electroretinography, fundus photography, fundus autofluorescence imaging, and optical coherence tomography. MAIN OUTCOME MEASURES:IDH3A variants, age at diagnosis, visual acuity, fundus appearance, visual field, and full-field electroretinography, fundus autofluorescence, and optical coherence tomography findings. RESULTS:We identified 7 different variants in IDH3A in 4 unrelated families, that is, 5 missense, 1 nonsense, and 1 frameshift variant. All participants showed symptoms early in life, ranging from night blindness to decreased visual acuity, and were diagnosed between the ages of 1 and 11 years. Four participants with biallelic IDH3A variants displayed a typical arRP phenotype and 3 participants were diagnosed with arRP and pseudocoloboma of the macula. CONCLUSIONS:IDH3A variants were identified as a novel cause of typical arRP in some individuals associated with macular pseudocoloboma. We observed both phenotypes in 2 siblings carrying the same compound heterozygous variants, which could be explained by variable disease expression and warrants caution when making assertions about genotype-phenotype correlations.

Inherited eye disorders have a large clinical and genetic heterogeneity, which makes genetic diagnosis cumbersome. An exome-sequencing approach was developed in which data analysis was divided into two steps: the vision gene panel and exome analysis. In the vision gene panel analysis, variants in genes known to cause inherited eye disorders were assessed for pathogenicity. If no causative variants were detected and when the patient consented, the entire exome data was analyzed. A total of 266 Dutch patients with different types of inherited eye disorders, including inherited retinal dystrophies, cataract, developmental eye disorders and optic atrophy, were investigated. In the vision gene panel analysis (likely), causative variants were detected in 49% and in the exome analysis in an additional 2% of the patients. The highest detection rate of (likely) causative variants was in patients with inherited retinal dystrophies, for instance a yield of 63% in patients with retinitis pigmentosa. In patients with developmental eye defects, cataract and optic atrophy, the detection rate was 50, 33 and 17%, respectively. An exome-sequencing approach enables a genetic diagnosis in patients with different types of inherited eye disorders using one test. The exome approach has the same detection rate as targeted panel sequencing tests, but offers a number of advantages. For instance, the vision gene panel can be frequently and easily updated with additional (novel) eye disorder genes. Determination of the genetic diagnosis improved the clinical diagnosis, regarding the assessment of the inheritance pattern as well as future disease perspective.

The Dutch Hereditary Cancer Registry was established in 1985 with the support of the Ministry of Health (VWS). The aims of the registry are: (1) to promote the identification of families with hereditary cancer, (2) to encourage the participation in surveillance programs of individuals at high risk, (3) to ensure the continuity of lifelong surveillance examinations, and (4) to promote research, in particular the improvement of surveillance protocols. During its early days the registry provided assistance with family investigations and the collection of medical data, and recommended surveillance when a family fulfilled specific diagnostic criteria. Since 2000 the registry has focused on family follow-up, and ensuring the quality of surveillance programs and appropriate clinical management. Since its founding, the registry has identified over 10,000 high-risk individuals with a diverse array of hereditary cancer syndromes. All were encouraged to participate in prevention programmes. The registry has published a number of studies that evaluated the outcome of surveillance protocols for colorectal cancer (CRC) in Lynch syndrome, as well as in familial colorectal cancer. In 2006, evaluation of the effect of registration and colonoscopic surveillance on the mortality rate associated with colorectal cancer (CRC) showed that the policy led to a substantial decrease in the mortality rate associated with CRC. Following discovery of MMR gene defects, the first predictive model that could select families for genetic testing was published by the Leiden group. In addition, over the years the registry has produced many cancer risk studies that have helped to develop appropriate surveillance protocols. Hereditary cancer registries in general, and the Lynch syndrome registry in particular, play an important role in improving the clinical management of affected families.

Complete interferon-γ receptor 1 (IFN-γR1) deficiency is a primary immunodeficiency causing predisposition to severe infection due to intracellular pathogens. Only 36 cases have been reported worldwide. The purpose of this article is to describe a large novel deletion found in 3 related cases, which resulted in the complete removal of the IFNGR1 gene.

Autosomal dominant polycystic kidney disease (ADPKD), characterized by the formation of numerous kidney cysts, is caused by PKD1 or PKD2 mutations and affects 0.1% of the population. Although recent clinical studies indicate that reduction of cAMP levels slows progression of PKD, this finding has not led to an established safe and effective therapy for patients, indicating the need to find new therapeutic targets. The role of TGF-β in PKD is not clearly understood, but nuclear accumulation of phosphorylated SMAD2/3 in cyst-lining cells suggests the involvement of TGF-β signaling in this disease. In this study, we ablated the TGF-β type 1 receptor (also termed activin receptor-like kinase 5) in renal epithelial cells of PKD mice, which had little to no effect on the expression of SMAD2/3 target genes or the progression of PKD. Therefore, we investigated whether alternative TGF-β superfamily ligands account for SMAD2/3 activation in cystic epithelial cells. Activins are members of the TGF-β superfamily and drive SMAD2/3 phosphorylation via activin receptors, but activins have not been studied in the context of PKD. Mice with PKD had increased expression of activin ligands, even at early stages of disease. In addition, treatment with a soluble activin receptor IIB fusion (sActRIIB-Fc) protein, which acts as a soluble trap to sequester activin ligands, effectively inhibited cyst formation in three distinct mouse models of PKD. These data point to activin signaling as a key pathway in PKD and a promising target for therapy.

Whole-exome sequencing of a patient with intellectual disability and without recognisable phenotype yielded a mutation in the intron20 splice donor site of CREBBP. Mutations at different positions within the same intron20 splice donor site were observed in three patients clinically suspected as having Rubinstein-Taybi syndrome (RSTS). All mutations were de novo and likely disease-causing. To investigate a putative difference in splicing between the patient without RSTS phenotype and the three patients with the RSTS phenotype, we analysed the effects of these mutations on splicing of the pre-mRNA of CREBBP. As no RNA of patients was available, we generated a new and improved exon-trap vector, pCDNAGHE, and tested the effect of the various mutations on splicing in vitro. All mutations lead to skipping of exon20. In one of the patients with an RSTS phenotype, there was also some normal splicing detectable. We conclude that the splicing pattern obtained by exon-trapping cannot explain the difference in phenotype between the patient without the RSTS phenotype and the patients with clinical RSTS. Patient or tissue-specific splice effects as well as modifying genes likely will explain the difference in phenotype.

Maturity-onset diabetes of the young (MODY) is the most common type of monogenic diabetes mellitus, estimated to account for approximately 1-4% of patients with diabetes. The predicted prevalence is, therefore, 20,000 patients in The Netherlands. Unfortunately less than 5% of these patients are confirmed by molecular genetic analysis. MODY is a clinically heterogeneous group of disorders caused by β-cell dysfunction, which is caused by mutations in multiple genes. MODY is characterized by an early onset of diabetes (often before the age of 30 years) and autosomal dominant inheritance. Patients do not usually require insulin at diagnosis. To emphasize the importance of genetic analysis we describe a 7-year-old boy and his siblings with MODY type 2. Molecular genetic testing is essential for individual patient care, as treatment options differ between the various forms of MODY; it also provides an opportunity to screen relatives.

Maturity-onset diabetes of the young (MODY) is the most common type of monogenic diabetes mellitus, estimated to account for approximately 1-4% of patients with diabetes. The predicted prevalence is, therefore, 20,000 patients in The Netherlands. Unfortunately less than 5% of these patients are confirmed by molecular genetic analysis. MODY is a clinically heterogeneous group of disorders caused by β-cell dysfunction, which is caused by mutations in multiple genes. MODY is characterized by an early onset of diabetes (often before the age of 30 years) and autosomal dominant inheritance. Patients do not usually require insulin at diagnosis. To emphasize the importance of genetic analysis we describe a 7-year-old boy and his siblings with MODY type 2. Molecular genetic testing is essential for individual patient care, as treatment options differ between the various forms of MODY; it also provides an opportunity to screen relatives.

Mutations in Polycystic Kidney Disease proteins (PKD1 or PKD2) are causative for autosomal dominant polycystic kidney disease (ADPKD). However, a small subset of ADPKD probands do not harbor a mutation in any of the known genes. Low density lipoprotein Receptor-related Protein 5 (LRP5) was recently associated with hepatic cystogenesis in isolated polycystic liver disease (PCLD). Here, we demonstrate that this gene may also have a role in unlinked and sporadic ADPKD patients. In a cohort of 79 unrelated patients with adult-onset ADPKD, we identified a total of four different LRP5 variants that were predicted to be pathogenic by in silico tools. One ADPKD patient has a positive family history for ADPKD and variant LRP5 c.1680G>T; p.(Trp560Cys) segregated with the disease. Although also two PKD1 variants probably affecting protein function were identified, luciferase activity assays presented for three LRP5 variants significant decreased signal activation of canonical Wnt signaling. This study contributes to the genetic spectrum of ADPKD. Introduction of the canonical Wnt signaling pathway provides new avenues for the study of the pathophysiology.

Succinate dehydrogenase (SDH) and fumarate hydratase (FH) are tricarboxylic acid (TCA) cycle enzymes and tumor suppressors. Loss-of-function mutations give rise to hereditary paragangliomas/pheochromocytomas and hereditary leiomyomatosis and renal cell carcinoma. Inactivation of SDH and FH results in an abnormal accumulation of their substrates succinate and fumarate, leading to inhibition of numerous α-ketoglutarate dependent dioxygenases, including histone demethylases and the ten-eleven-translocation (TET) family of 5-methylcytosine (5 mC) hydroxylases. To evaluate the distribution of DNA and histone methylation, we used immunohistochemistry to analyze the expression of 5 mC, 5-hydroxymethylcytosine (5 hmC), TET1, H3K4me3, H3K9me3, and H3K27me3 on tissue microarrays containing paragangliomas/pheochromocytomas (n = 134) and hereditary and sporadic smooth muscle tumors (n = 56) in comparison to their normal counterparts. Our results demonstrate distinct loss of 5 hmC in tumor cells in SDH- and FH-deficient tumors. Loss of 5 hmC in SDH-deficient tumors was associated with nuclear exclusion of TET1, a known regulator of 5 hmC levels. Moreover, increased methylation of H3K9me3 occurred predominantly in the chief cell component of SDH mutant tumors, while no changes were seen in H3K4me3 and H3K27me3, data supported by in vitro knockdown of SDH genes. We also show for the first time that FH-deficient smooth muscle tumors exhibit increased H3K9me3 methylation compared to wildtype tumors. Our findings reveal broadly similar patterns of epigenetic deregulation in both FH- and SDH-deficient tumors, suggesting that defects in genes of the TCA cycle result in common mechanisms of inhibition of histone and DNA demethylases.

To the Editor: It was not our intention to offend any medical professionals in India and certainly not to show the Indian medical community in a bad light, as suggested by Dalal et al.1.Dalal A.B. Ranganath P. Phadke S.R. Prenatal diagnosis in India is not limited to sex selection.10.1038/gim.2014.149Genet Med. 2015; 17: 88Google Scholar in their letter, “Prenatal Diagnosis in India Is Not Limited to Sex Selection” (this issue). We stated at the outset of our article2.Madan K. Breuning M.H. Impact of prenatal technologies on the sex ratio in India: an overview.10.1038/gim.2013.172Genet Med. 2014; 16: 425-432Google Scholar that prenatal diagnosis (PD) is legitimately used in India for diagnosing a wide range of genetic diseases. We have also stated that selective feticide concerns only 2–4% of pregnancies carrying a girl, but the numbers are large in absolute terms.3.Jha S. Kesler M.A. Kumar R. Trends in selective abortions of girls in India: analysis of nationally representative birth histories from 1990 to 2005 and census data from 1991 to 2011.10.1016/S0140-6736(11)60649-1Lancet. 2011; 377: 1921-1928Google Scholar It is therefore unfortunate that Dalal et al.1.Dalal A.B. Ranganath P. Phadke S.R. Prenatal diagnosis in India is not limited to sex selection.10.1038/gim.2014.149Genet Med. 2015; 17: 88Google Scholar are offended by some of these statements. The statements in our review are amply supported by references to the vast number of papers and books published on the subject, 70% of which report work carried out in India by Indian authors. Below we address the points raised by Dalal and colleagues.1.Dalal A.B. Ranganath P. Phadke S.R. Prenatal diagnosis in India is not limited to sex selection.10.1038/gim.2014.149Genet Med. 2015; 17: 88Google ScholarDalal et al.1.Dalal A.B. Ranganath P. Phadke S.R. Prenatal diagnosis in India is not limited to sex selection.10.1038/gim.2014.149Genet Med. 2015; 17: 88Google Scholar are offended by the statements “Prenatal diagnosis was introduced in India as a method for detecting fetal abnormalities, but was soon used mainly for prenatal sex selection.4.Allahbadia G.N. The 50 million missing women.10.1023/A:1016859622724J Assist Reprod Genet. 2002; 19: 411-416Google Scholar,5.Tandon SL, Sharma R. Female foeticide and infanticide in India: an analysis of crimes against girl children. Int J Crim Justice Sci 2006. http://www.sascv.org/ijcjs/previousissues.html. Accessed 8 August 2013.Google Scholar The Indian medical profession actively promoted it for this purpose.6.George S.M. Millions of missing girls: from fetal sexing to high technology sex selection in India.10.1002/pd.1475Prenat Diagn. 2006; 26: 604-609Google Scholar,7.Sharma B.R. Gupta N. Relhan N. Misuse of prenatal diagnostic technology for sex-selected abortions and its consequences in India.1:STN:280:DC%2BD2snit1GmtQ%3D%3D10.1016/j.puhe.2007.03.004Public Health. 2007; 121: 854-860Google Scholar,8.Aravamudan G. Penguin Books.Disappearing Daughters: The Tragedy of Female Foeticide. New Delhi, India, 2007Google Scholar,9.Lancet India Correspondent Misuse of amniocentesis.10.1016/S0140-6736(83)91863-9Lancet. 1983; 321: 812-813Google Scholar” They claim that the second sentence is not true. We quote from four references, as follows. (i) “Eminent medical researchers who pioneered amniocentesis at the prestigious All India Institute of Medical Sciences advocated fetal sexing 30 years ago, arguing that it would assist those Indian women who repeatedly reproduce just to have a son.... Subsequently, sex selection was promoted as population control method.... Doctors wanted the government to promote sex determination techniques to reduce population growth.”6 (ii) “Investigation... showed that in a large public hospital in [Bombay] there had been 7800 requests for amniocentesis in the past five years. Only 5% were for detection of genetic defects and about 1% of women wanted to get rid of a male fetus. All the others sought amniocentesis with the express purpose of aborting female foetuses.”9.Lancet India Correspondent Misuse of amniocentesis.10.1016/S0140-6736(83)91863-9Lancet. 1983; 321: 812-813Google Scholar (iii) “Eighty-four percent of gynecologists admitted to having performed amniocentesis tests for sex determination.... The overwhelming majority of “patients”... were only interested in knowing the sex of the fetus.”5.Tandon SL, Sharma R. Female foeticide and infanticide in India: an analysis of crimes against girl children. Int J Crim Justice Sci 2006. http://www.sascv.org/ijcjs/previousissues.html. Accessed 8 August 2013.Google Scholar (iv) “Amniocentesis was first introduced in India in 1974.... It caught on like wildfire because right from the start, it was misused by doctors mostly to detect the sex of the baby in the womb.”8.Aravamudan G. Penguin Books.Disappearing Daughters: The Tragedy of Female Foeticide. New Delhi, India, 2007Google Scholar For more details on the role of the doctors, see refs. 4.Allahbadia G.N. The 50 million missing women.10.1023/A:1016859622724J Assist Reprod Genet. 2002; 19: 411-416Google Scholar,5.Tandon SL, Sharma R. Female foeticide and infanticide in India: an analysis of crimes against girl children. Int J Crim Justice Sci 2006. http://www.sascv.org/ijcjs/previousissues.html. Accessed 8 August 2013.Google Scholar,6.George S.M. Millions of missing girls: from fetal sexing to high technology sex selection in India.10.1002/pd.1475Prenat Diagn. 2006; 26: 604-609Google Scholar,7.Sharma B.R. Gupta N. Relhan N. Misuse of prenatal diagnostic technology for sex-selected abortions and its consequences in India.1:STN:280:DC%2BD2snit1GmtQ%3D%3D10.1016/j.puhe.2007.03.004Public Health. 2007; 121: 854-860Google Scholar,8.Aravamudan G. Penguin Books.Disappearing Daughters: The Tragedy of Female Foeticide. New Delhi, India, 2007Google Scholar,9.Lancet India Correspondent Misuse of amniocentesis.10.1016/S0140-6736(83)91863-9Lancet. 1983; 321: 812-813Google Scholar,10.Subramanian S.V. Corsi D.J. Can India achieve a balance of sexes at birth?.1:STN:280:DC%2BC3MrnsFylsA%3D%3D10.1016/S0140-6736(11)60709-5Lancet. 2011; 377: 1893-1894Google Scholar,11.Oomman N. Ganatra B.R. Sex selection: the systematic elimination of girls.10.1016/S0968-8080(02)00029-0Reprod Health Matters. 2002; 10: 184-188Google Scholar,12.Mudur G. Doctors in India prosecuted for sex determination, but few convicted.16455711BMJ. 2006; 332: 257Google Scholar,13.Karat B, Gessorge S. Dont trash this law, the fault lies in non-implementation. The Hindu, 4 February 2012. http://www.thehindu.com/opinion/op-ed/dont-trash-this-law-the-fault-lies-in-nonimplementation/article2858004.ece. Accessed 8 August 2013.Google Scholar.The book by Aravamudan,8.Aravamudan G. Penguin Books.Disappearing Daughters: The Tragedy of Female Foeticide. New Delhi, India, 2007Google Scholar with a foreword by the former president of India, Abdul Kalam, gives an account of a 10-year field study in India. Large-scale involvement of medical professionals is indicated by the following. In the 1980s, almost 100% of 15,914 and 8,000 abortions in a Bombay abortion center and six city hospitals, respectively, were of female fetuses.5.Tandon SL, Sharma R. Female foeticide and infanticide in India: an analysis of crimes against girl children. Int J Crim Justice Sci 2006. http://www.sascv.org/ijcjs/previousissues.html. Accessed 8 August 2013.Google Scholar Even after the Pre-Natal Diagnostic Techniques Act of 1994 banning the use of PD for sex selection, the child sex ratio has continued to deteriorate sharply, from 945 girls for every 1,000 boys in 1991 to 914 in 2011. The figures from the 2011 census, supported by a 15-year study published in The Lancet,3.Jha S. Kesler M.A. Kumar R. Trends in selective abortions of girls in India: analysis of nationally representative birth histories from 1990 to 2005 and census data from 1991 to 2011.10.1016/S0140-6736(11)60649-1Lancet. 2011; 377: 1921-1928Google Scholar show that the problem of skewed sex ratio has spread to nearly all the states in India. However, although the absolute number of individuals involved may be large, it probably forms a small proportion of medical professionals. Undoubtedly, the vast majority of medical professionals are in no way involved in illegal practices.We examined the data to see whether we could find support for the suggestion that rape and crime against women in India7.Sharma B.R. Gupta N. Relhan N. Misuse of prenatal diagnostic technology for sex-selected abortions and its consequences in India.1:STN:280:DC%2BD2snit1GmtQ%3D%3D10.1016/j.puhe.2007.03.004Public Health. 2007; 121: 854-860Google Scholar,11.Oomman N. Ganatra B.R. Sex selection: the systematic elimination of girls.10.1016/S0968-8080(02)00029-0Reprod Health Matters. 2002; 10: 184-188Google Scholar,14.Deshpande J.D. Phalke D.B. Phalke V.D. Prenatal sex determination: issues and concerns.Pravara Med Rev. 2009; 1: 4-6Google Scholar and China15.Lai-wan C.C. Blyth E. Hoi-yan C.C. Attitudes to and practices regarding sex selection in China.10.1002/pd.1477Prenat Diagn. 2006; 26: 610-613Google Scholar,16.Hesketh T. Lu L. Xing Z.W. The effect of Chinas one-child family policy after 25 years.1:CAS:528:DC%2BD2MXhtVWhsbbI10.1056/NEJMhpr051833N Engl J Med. 2005; 353: 1171-1176Google Scholar may be related to the shortage of women. We did not find a correlation, except in 4 of 35 states. We did not state that crime against women is directly attributed to PD and sex selection.Mention of both child marriages and dowry deaths is relevant. The exceptionally high rate of child marriages in India (47%)17.UNICEF. UNICEF India Statistics, child protection 2012. http://www.unicef.org/infobycountry/insdia_statistics.html. Accessed 8 August 2013.Google Scholar contributes, however slightly, to further skewing of the sex ratio because of the high rate of death among teenage girls during childbirth;18.ICRW. Child marriage facts and figures. The International Centre for Research on Women 2012. http://www.icrw.org/child-marriage-facts-and-figures. Accessed 8 August 2013.Google Scholar it also indicates the low status of women. One of the most stated reasons for selective abortions of girls is the dowry system. Dowry deaths indicate extreme situations, which cause even greater pressure for sex-selective abortions. With estimates of 15,000 to 25,000 per year,19.Banerji R. Sex and Power Defining History, Shaping Societies. Penguin Books, 2008Google Scholar dowry deaths also contribute to the skewed sex ratio. We quoted the slogan used by medical professionals to advertise PD for sex selection in the 1980s and 1990s.4.Allahbadia G.N. The 50 million missing women.10.1023/A:1016859622724J Assist Reprod Genet. 2002; 19: 411-416Google Scholar,7.Sharma B.R. Gupta N. Relhan N. Misuse of prenatal diagnostic technology for sex-selected abortions and its consequences in India.1:STN:280:DC%2BD2snit1GmtQ%3D%3D10.1016/j.puhe.2007.03.004Public Health. 2007; 121: 854-860Google Scholar,8.Aravamudan G. Penguin Books.Disappearing Daughters: The Tragedy of Female Foeticide. New Delhi, India, 2007Google Scholar,14.Deshpande J.D. Phalke D.B. Phalke V.D. Prenatal sex determination: issues and concerns.Pravara Med Rev. 2009; 1: 4-6Google Scholar It is only by acknowledging these facts, not ignoring them, that one can hope to bring about change.Dalal et al.1.Dalal A.B. Ranganath P. Phadke S.R. Prenatal diagnosis in India is not limited to sex selection.10.1038/gim.2014.149Genet Med. 2015; 17: 88Google Scholar are right in correcting us: The matriarchal system is not followed in all the southern states but only in parts of Kerala.We did make an important novel suggestion to address the problem: compulsory targeted education addressing all aspects of the subject starting at a very young age in primary school and continuing until the end of secondary school. This may have the desired effect in 10–15 years and might be the quickest way to effect change in the culture.At the time of the writing of our review in 2013, very little attention had been paid to this issue by politicians in India. We were therefore very pleased that during his Independence Day speech on 15 August 2014, the newly elected prime minister of India, Narendra Modi, directly addressed the question of the skewed sex ratio: “I request the doctors not to kill the girl growing in the womb of a mother just to line their own pockets. I advise mothers and sisters not to sacrifice daughters in the hope of [a] son.” (The full text of Mr. Modi’s speech is available at http://indiatoday.intoday.in/story/narendra-modi-independence-day-speech-full-text-red-fort/1/377299.html.) This is an encouraging sign.DisclosureThe authors declare no conflict of interest. To the Editor: It was not our intention to offend any medical professionals in India and certainly not to show the Indian medical community in a bad light, as suggested by Dalal et al.1.Dalal A.B. Ranganath P. Phadke S.R. Prenatal diagnosis in India is not limited to sex selection.10.1038/gim.2014.149Genet Med. 2015; 17: 88Google Scholar in their letter, “Prenatal Diagnosis in India Is Not Limited to Sex Selection” (this issue). We stated at the outset of our article2.Madan K. Breuning M.H. Impact of prenatal technologies on the sex ratio in India: an overview.10.1038/gim.2013.172Genet Med. 2014; 16: 425-432Google Scholar that prenatal diagnosis (PD) is legitimately used in India for diagnosing a wide range of genetic diseases. We have also stated that selective feticide concerns only 2–4% of pregnancies carrying a girl, but the numbers are large in absolute terms.3.Jha S. Kesler M.A. Kumar R. Trends in selective abortions of girls in India: analysis of nationally representative birth histories from 1990 to 2005 and census data from 1991 to 2011.10.1016/S0140-6736(11)60649-1Lancet. 2011; 377: 1921-1928Google Scholar It is therefore unfortunate that Dalal et al.1.Dalal A.B. Ranganath P. Phadke S.R. Prenatal diagnosis in India is not limited to sex selection.10.1038/gim.2014.149Genet Med. 2015; 17: 88Google Scholar are offended by some of these statements. The statements in our review are amply supported by references to the vast number of papers and books published on the subject, 70% of which report work carried out in India by Indian authors. Below we address the points raised by Dalal and colleagues.1.Dalal A.B. Ranganath P. Phadke S.R. Prenatal diagnosis in India is not limited to sex selection.10.1038/gim.2014.149Genet Med. 2015; 17: 88Google Scholar Dalal et al.1.Dalal A.B. Ranganath P. Phadke S.R. Prenatal diagnosis in India is not limited to sex selection.10.1038/gim.2014.149Genet Med. 2015; 17: 88Google Scholar are offended by the statements “Prenatal diagnosis was introduced in India as a method for detecting fetal abnormalities, but was soon used mainly for prenatal sex selection.4.Allahbadia G.N. The 50 million missing women.10.1023/A:1016859622724J Assist Reprod Genet. 2002; 19: 411-416Google Scholar,5.Tandon SL, Sharma R. Female foeticide and infanticide in India: an analysis of crimes against girl children. Int J Crim Justice Sci 2006. http://www.sascv.org/ijcjs/previousissues.html. Accessed 8 August 2013.Google Scholar The Indian medical profession actively promoted it for this purpose.6.George S.M. Millions of missing girls: from fetal sexing to high technology sex selection in India.10.1002/pd.1475Prenat Diagn. 2006; 26: 604-609Google Scholar,7.Sharma B.R. Gupta N. Relhan N. Misuse of prenatal diagnostic technology for sex-selected abortions and its consequences in India.1:STN:280:DC%2BD2snit1GmtQ%3D%3D10.1016/j.puhe.2007.03.004Public Health. 2007; 121: 854-860Google Scholar,8.Aravamudan G. Penguin Books.Disappearing Daughters: The Tragedy of Female Foeticide. New Delhi, India, 2007Google Scholar,9.Lancet India Correspondent Misuse of amniocentesis.10.1016/S0140-6736(83)91863-9Lancet. 1983; 321: 812-813Google Scholar” They claim that the second sentence is not true. We quote from four references, as follows. (i) “Eminent medical researchers who pioneered amniocentesis at the prestigious All India Institute of Medical Sciences advocated fetal sexing 30 years ago, arguing that it would assist those Indian women who repeatedly reproduce just to have a son.... Subsequently, sex selection was promoted as population control method.... Doctors wanted the government to promote sex determination techniques to reduce population growth.”6 (ii) “Investigation... showed that in a large public hospital in [Bombay] there had been 7800 requests for amniocentesis in the past five years. Only 5% were for detection of genetic defects and about 1% of women wanted to get rid of a male fetus. All the others sought amniocentesis with the express purpose of aborting female foetuses.”9.Lancet India Correspondent Misuse of amniocentesis.10.1016/S0140-6736(83)91863-9Lancet. 1983; 321: 812-813Google Scholar (iii) “Eighty-four percent of gynecologists admitted to having performed amniocentesis tests for sex determination.... The overwhelming majority of “patients”... were only interested in knowing the sex of the fetus.”5.Tandon SL, Sharma R. Female foeticide and infanticide in India: an analysis of crimes against girl children. Int J Crim Justice Sci 2006. http://www.sascv.org/ijcjs/previousissues.html. Accessed 8 August 2013.Google Scholar (iv) “Amniocentesis was first introduced in India in 1974.... It caught on like wildfire because right from the start, it was misused by doctors mostly to detect the sex of the baby in the womb.”8.Aravamudan G. Penguin Books.Disappearing Daughters: The Tragedy of Female Foeticide. New Delhi, India, 2007Google Scholar For more details on the role of the doctors, see refs. 4.Allahbadia G.N. The 50 million missing women.10.1023/A:1016859622724J Assist Reprod Genet. 2002; 19: 411-416Google Scholar,5.Tandon SL, Sharma R. Female foeticide and infanticide in India: an analysis of crimes against girl children. Int J Crim Justice Sci 2006. http://www.sascv.org/ijcjs/previousissues.html. Accessed 8 August 2013.Google Scholar,6.George S.M. Millions of missing girls: from fetal sexing to high technology sex selection in India.10.1002/pd.1475Prenat Diagn. 2006; 26: 604-609Google Scholar,7.Sharma B.R. Gupta N. Relhan N. Misuse of prenatal diagnostic technology for sex-selected abortions and its consequences in India.1:STN:280:DC%2BD2snit1GmtQ%3D%3D10.1016/j.puhe.2007.03.004Public Health. 2007; 121: 854-860Google Scholar,8.Aravamudan G. Penguin Books.Disappearing Daughters: The Tragedy of Female Foeticide. New Delhi, India, 2007Google Scholar,9.Lancet India Correspondent Misuse of amniocentesis.10.1016/S0140-6736(83)91863-9Lancet. 1983; 321: 812-813Google Scholar,10.Subramanian S.V. Corsi D.J. Can India achieve a balance of sexes at birth?.1:STN:280:DC%2BC3MrnsFylsA%3D%3D10.1016/S0140-6736(11)60709-5Lancet. 2011; 377: 1893-1894Google Scholar,11.Oomman N. Ganatra B.R. Sex selection: the systematic elimination of girls.10.1016/S0968-8080(02)00029-0Reprod Health Matters. 2002; 10: 184-188Google Scholar,12.Mudur G. Doctors in India prosecuted for sex determination, but few convicted.16455711BMJ. 2006; 332: 257Google Scholar,13.Karat B, Gessorge S. Dont trash this law, the fault lies in non-implementation. The Hindu, 4 February 2012. http://www.thehindu.com/opinion/op-ed/dont-trash-this-law-the-fault-lies-in-nonimplementation/article2858004.ece. Accessed 8 August 2013.Google Scholar. The book by Aravamudan,8.Aravamudan G. Penguin Books.Disappearing Daughters: The Tragedy of Female Foeticide. New Delhi, India, 2007Google Scholar with a foreword by the former president of India, Abdul Kalam, gives an account of a 10-year field study in India. Large-scale involvement of medical professionals is indicated by the following. In the 1980s, almost 100% of 15,914 and 8,000 abortions in a Bombay abortion center and six city hospitals, respectively, were of female fetuses.5.Tandon SL, Sharma R. Female foeticide and infanticide in India: an analysis of crimes against girl children. Int J Crim Justice Sci 2006. http://www.sascv.org/ijcjs/previousissues.html. Accessed 8 August 2013.Google Scholar Even after the Pre-Natal Diagnostic Techniques Act of 1994 banning the use of PD for sex selection, the child sex ratio has continued to deteriorate sharply, from 945 girls for every 1,000 boys in 1991 to 914 in 2011. The figures from the 2011 census, supported by a 15-year study published in The Lancet,3.Jha S. Kesler M.A. Kumar R. Trends in selective abortions of girls in India: analysis of nationally representative birth histories from 1990 to 2005 and census data from 1991 to 2011.10.1016/S0140-6736(11)60649-1Lancet. 2011; 377: 1921-1928Google Scholar show that the problem of skewed sex ratio has spread to nearly all the states in India. However, although the absolute number of individuals involved may be large, it probably forms a small proportion of medical professionals. Undoubtedly, the vast majority of medical professionals are in no way involved in illegal practices. We examined the data to see whether we could find support for the suggestion that rape and crime against women in India7.Sharma B.R. Gupta N. Relhan N. Misuse of prenatal diagnostic technology for sex-selected abortions and its consequences in India.1:STN:280:DC%2BD2snit1GmtQ%3D%3D10.1016/j.puhe.2007.03.004Public Health. 2007; 121: 854-860Google Scholar,11.Oomman N. Ganatra B.R. Sex selection: the systematic elimination of girls.10.1016/S0968-8080(02)00029-0Reprod Health Matters. 2002; 10: 184-188Google Scholar,14.Deshpande J.D. Phalke D.B. Phalke V.D. Prenatal sex determination: issues and concerns.Pravara Med Rev. 2009; 1: 4-6Google Scholar and China15.Lai-wan C.C. Blyth E. Hoi-yan C.C. Attitudes to and practices regarding sex selection in China.10.1002/pd.1477Prenat Diagn. 2006; 26: 610-613Google Scholar,16.Hesketh T. Lu L. Xing Z.W. The effect of Chinas one-child family policy after 25 years.1:CAS:528:DC%2BD2MXhtVWhsbbI10.1056/NEJMhpr051833N Engl J Med. 2005; 353: 1171-1176Google Scholar may be related to the shortage of women. We did not find a correlation, except in 4 of 35 states. We did not state that crime against women is directly attributed to PD and sex selection. Mention of both child marriages and dowry deaths is relevant. The exceptionally high rate of child marriages in India (47%)17.UNICEF. UNICEF India Statistics, child protection 2012. http://www.unicef.org/infobycountry/insdia_statistics.html. Accessed 8 August 2013.Google Scholar contributes, however slightly, to further skewing of the sex ratio because of the high rate of death among teenage girls during childbirth;18.ICRW. Child marriage facts and figures. The International Centre for Research on Women 2012. http://www.icrw.org/child-marriage-facts-and-figures. Accessed 8 August 2013.Google Scholar it also indicates the low status of women. One of the most stated reasons for selective abortions of girls is the dowry system. Dowry deaths indicate extreme situations, which cause even greater pressure for sex-selective abortions. With estimates of 15,000 to 25,000 per year,19.Banerji R. Sex and Power Defining History, Shaping Societies. Penguin Books, 2008Google Scholar dowry deaths also contribute to the skewed sex ratio. We quoted the slogan used by medical professionals to advertise PD for sex selection in the 1980s and 1990s.4.Allahbadia G.N. The 50 million missing women.10.1023/A:1016859622724J Assist Reprod Genet. 2002; 19: 411-416Google Scholar,7.Sharma B.R. Gupta N. Relhan N. Misuse of prenatal diagnostic technology for sex-selected abortions and its consequences in India.1:STN:280:DC%2BD2snit1GmtQ%3D%3D10.1016/j.puhe.2007.03.004Public Health. 2007; 121: 854-860Google Scholar,8.Aravamudan G. Penguin Books.Disappearing Daughters: The Tragedy of Female Foeticide. New Delhi, India, 2007Google Scholar,14.Deshpande J.D. Phalke D.B. Phalke V.D. Prenatal sex determination: issues and concerns.Pravara Med Rev. 2009; 1: 4-6Google Scholar It is only by acknowledging these facts, not ignoring them, that one can hope to bring about change. Dalal et al.1.Dalal A.B. Ranganath P. Phadke S.R. Prenatal diagnosis in India is not limited to sex selection.10.1038/gim.2014.149Genet Med. 2015; 17: 88Google Scholar are right in correcting us: The matriarchal system is not followed in all the southern states but only in parts of Kerala. We did make an important novel suggestion to address the problem: compulsory targeted education addressing all aspects of the subject starting at a very young age in primary school and continuing until the end of secondary school. This may have the desired effect in 10–15 years and might be the quickest way to effect change in the culture. At the time of the writing of our review in 2013, very little attention had been paid to this issue by politicians in India. We were therefore very pleased that during his Independence Day speech on 15 August 2014, the newly elected prime minister of India, Narendra Modi, directly addressed the question of the skewed sex ratio: “I request the doctors not to kill the girl growing in the womb of a mother just to line their own pockets. I advise mothers and sisters not to sacrifice daughters in the hope of [a] son.” (The full text of Mr. Modi’s speech is available at http://indiatoday.intoday.in/story/narendra-modi-independence-day-speech-full-text-red-fort/1/377299.html.) This is an encouraging sign. DisclosureThe authors declare no conflict of interest. The authors declare no conflict of interest.

Genetic testing for maturity-onset diabetes of the young (MODY) may be relevant for treatment and prognosis in patients with usually early-onset, non-ketotic, insulin-sensitive diabetes and for monitoring strategies in non-diabetic mutation carriers. This study describes the first 10 years of genetic testing for MODY in The Netherlands in terms of volume and test positive rate, medical setting, purpose of the test and age of patients tested. Some analyses focus on the most prevalent subtype, HNF1A MODY. Data were retrospectively extracted from a laboratory database. In total, 502 individuals were identified with a pathogenic mutation in HNF4A, GCK or HNF1A between 2001 and 2010. Although mutation scanning for MODY was used at an increasing rate, cascade testing was only used for one relative, on average, per positive index patient. Testing for HNF1A MODY was mostly requested by internists and paediatricians, often from regional hospitals. Primary care physicians and clinical geneticists rarely requested genetic testing for HNF1A MODY. Clinical geneticists requested cascade testing relatively more often than other health professionals. A substantial proportion (currently 29%) of HNF1A MODY probands was at least 40 years old at the time of testing. In conclusion, the number of individuals genetically tested for MODY so far in The Netherlands is low compared with previously predicted numbers of patients. Doctors' valuation of the test and patients' and family members' response to (an offer of) genetic testing on the other hand need to be investigated. Efforts may be needed to develop and implement translational guidelines.

BACKGROUND/AIMS:In addition to genome-wide association studies (GWAS), height-associated genes may be uncovered by studying individuals with extreme short or tall stature. METHODS:Genome-wide analysis for copy number variants (CNVs), using single nucleotide polymorphism (SNP) arrays, was performed in 49 index cases born small for gestational age with persistent short stature. Segregation analysis was performed, and genes in CNVs were compared with information from GWAS, gene expression in rodents' growth plates, and published information. RESULTS:CNVs were detected in 13 cases. In 5 children a known cause of short stature was found: UPD7, UPD14, a duplication of the SHOX enhancer region, an IGF1R deletion, and a 22q11.21 deletion. In the remaining 8 cases, potential pathogenic CNVs were detected, either de novo (n = 1), segregating (n = 2), or not segregating with short stature (n = 5). Bioinformatic analysis of the de novo and segregating CNVs suggested that HOXD4, AGPS, PDE11A, OSBPL6, PRKRA and PLEKHA3, and possibly DGKB and TNFRSF11B are potential candidate genes. A SERPINA7 or NRK defect may be associated with an X-linked form of short stature. CONCLUSION:SNP arrays detected 5 known causes of short stature with prenatal onset and suggested several potential candidate genes.

Microdeletions in the 15q22 region have not been well documented. We collected genotype and phenotype data from five patients with microdeletions involving 15q22.2, which were between 0.7 Mb and 6.5 Mb in size; two were of de novo origin and one was of familial origin. Intellectual disability and epilepsy are frequently observed in patients with 15q22.2 deletions. Genotype-phenotype correlation analysis narrowed the critical region for such neurologic symptoms to a genomic region of 654 Kb including the NMDA receptor-regulated 2 gene (NARG2) and the PAR-related orphan receptor A gene (RORA), either of which may be responsible for neurological symptoms commonly observed in patients with deletions in this region. The neighboring regions, including the forkhead box B1 gene (FOXB1), may also be related to the additional neurological features observed in the patients with larger deletions.

In total, 1 in 1000 individuals carries a germline mutation in the PKD1 or PKD2 gene, which leads to autosomal dominant polycystic kidney disease (ADPKD). Cysts can form early in life and progressively increase in number and size during adulthood. Extensive research has led to the presumption that somatic inactivation of the remaining allele initiates the formation of cysts, and the progression is further accelerated by renal injury. However, this hypothesis is primarily on the basis of animal studies, in which the gene is inactivated simultaneously in large percentages of kidney cells. To mimic human ADPKD in mice more precisely, we reduced the percentage of Pkd1-deficient kidney cells to 8%. Notably, no pathologic changes occurred for 6 months after Pkd1 deletion, and additional renal injury increased the likelihood of cyst formation but never triggered rapid PKD. In mildly affected mice, cysts were not randomly distributed throughout the kidney but formed in clusters, which could be explained by increased PKD-related signaling in not only cystic epithelial cells but also, healthy-appearing tubules near cysts. In the majority of mice, these changes preceded a rapid and massive onset of severe PKD that was remarkably similar to human ADPKD. Our data suggest that initial cysts are the principal trigger for a snowball effect driving the formation of new cysts, leading to the progression of severe PKD. In addition, this approach is a suitable model for mimicking human ADPKD and can be used for preclinical testing.

Many patients with Maturity-Onset Diabetes of the Young (MODY) are currently undiagnosed or misdiagnosed with type 1 or 2 diabetes. A genetic diagnosis enables appropriate treatment of patients and monitoring of presymptomatic family members.

Height is a highly heritable and classic polygenic trait. Recent genome-wide association studies (GWAS) have revealed that at least 180 genetic variants influence adult height. However, these variants explain only about 10% of the phenotypic variation in height. Genetic analysis of short individuals can lead to the discovery of novel rare gene defects with a large effect on growth. In an effort to identify novel genes associated with short stature, genome-wide analysis for copy number variants (CNVs), using single-nucleotide polymorphism arrays, in 162 patients (149 families) with short stature was performed. Segregation analysis was performed if possible, and genes in CNVs were compared with information from GWAS, gene expression in rodents' growth plates and published information. CNVs were detected in 40 families. In six families, a known cause of short stature was found (SHOX deletion or duplication, IGF1R deletion), in two combined with a de novo potentially pathogenic CNV. Thirty-three families had one or more potentially pathogenic CNVs (n=40). In 24 of these families, segregation analysis could be performed, identifying three de novo CNVs and nine CNVs segregating with short stature. Four were located near loci associated with height in GWAS (ADAMTS17, TULP4, PRKG2/BMP3 and PAPPA). Besides six CNVs known to be causative for short stature, 40 CNVs with possible pathogenicity were identified. Segregation studies and bioinformatics analysis suggested various potential candidate genes.