Reversal of Clinical Phenotype of Sotos Syndrome Due to Microduplication of NSD1 Gene.

Sotos syndrome is caused by heterozygous pathogenic variants or deletions in the long arm of chromosome 5 encompassing NSD1. The cardinal features of this condition are overgrowth, macrocephaly, and intellectual disability. Conversely, duplications leading to an extra copy of NSD1 result in a reverse phenotype that is observed in duplication/microduplication of the 5q region. An 11-y-old boy was referred to the genetics clinic in view of global developmental delay and general tonic-clonic seizures. Whole-exome sequencing revealed the presence of likely pathogenic copy number variation, a contiguous duplication of size ~4.11 Mb spanning genomic location chr5: g.(?_171773956)_(175880045_?)dup. After validation by multiplex ligation-dependent probe amplification (MLPA) and phenotypic correlation, a diagnosis of reverse Sotos syndrome was confirmed. As far as the authors know, this is the first patient report of reverse Sotos syndrome from India. It highlights the peculiar presentation of this disorder as well as discusses the increasing potential of exome sequencing to screen for copy number variations (CNVs).

Computational biology insights into genotype-clinical phenotype-protein phenotype relationships between novel SLC26A2 variants identified in inherited skeletal dysplasias.

BACKGROUND: Pathogenic variants in the transmembrane sulfate transporter protein SLC26A2 are associated with different phenotypes of inherited chondrodysplasias. As limited data is published from India, in this study we sought to elucidate the molecular basis of inherited chondrodysplasias in an Indian cohort. METHODS: Molecular screening of 32 fetuses with antenatally diagnosed lethal skeletal dysplasia was performed by next generation sequencing and Sanger sequencing. The genotype-protein phenotype characterization was done using computational biology techniques like homology modelling, stability and pathogenicity predictions. RESULTS: We identified five rare autosomal recessive SLC26A2 [NM_000112.4] variants, including three homozygous c.796dupA(p.Thr266Asnfs*12), c.1724delA(p.Lys575Serfs*10), and c.1375_1377dup(p.Val459dup) and two heterozygous variants (c.532C > T(p.Arg178*)) and (c.1382C > T(p.Ala461Val)) in compound heterozygous form in a total of four foetuses. Genotype-protein phenotype annotations highlighted that the clinically severe achondrogenesis 1B causative c.796dupA(p.Thr266Asnfs*12) and c.1724delA(p.Lys575Serfs*10)variants impact SLC26A2 protein structure by deletion of the protein core and transmembrane STAS domains, respectively. In clinically moderate atelosteogenesis type 2 phenotype, the c.1382C > T(p.Ala461Val) variant is predicted to distort alpha helix conformation and alter the bonding properties and free energy dynamics of transmembrane domains and the c.532C > T(p.Arg178*) variant results in loss of both core transmembrane and STAS domains of the SLC26A2 protein. The c.1375_1377dup(p.Val459dup) variant identified in clinically milder atelosteogenesis type II-diastrophic dysplasia spectrum lethal phenotype is predicted to decrease the Qualitative Model Energy Analysis (QMean), which affects major geometrical aspects of the SLC26A2 protein structure. CONCLUSION: We expand the spectrum of SLC26A2 related lethal chondrodysplasia and report three novel variants correlating clinical severity and protein phenotype within the lethal spectrum of this rare dysplasia. We demonstrate the relevance of structural characterization to aid novel variant reclassification to provide better prenatal management and reproductive options to families with lethal antenatal skeletal disorder.

Levels of Lyso GL-1 in Gaucher and Lyso GL-3 in Fabry patients from India: Diagnostic aids for these lysosomal storage disorders.

BACKGROUND & AIMS: Lysosomal storage disorders (LSDs) remain a significant cause of morbidity in the Indian population and treatment is largely out of reach for most patients. Although data on enzymatic and molecular diagnosis of Gaucher disease (GD) and Fabry disease (FD) in Indian patients are available, the present study intended to establish the pathogenic levels of Lyso GL-1 and Lyso GL-3 in patients of GD and FD respectively as diagnostic aids. MATERIALS AND METHODS: From 2017 to 2019, ninety confirmed Gaucher cases (by enzymatic and molecular analysis) were tested for chitotriosidase (fluorometrically) and Lyso GL-1 (LC-MS/MS) and ten confirmed Fabry cases were analyzed for Lyso GL-3 (LC-MS/MS). RESULTS: Lyso GL-1 (median: 685.5 ng/mL, cut-off: 14) and Lyso GL-3 (median: 75.6 ng/mL, cut-off: 3.5) were found to be elevated in all enzymatically deficient patients of GD and FD respectively, however, no specific trend was observed between the levels of these biomarkers and the pathogenic variant(s) present in the patients of these disorders. CONCLUSIONS: This is the first report on Lyso GL-1 and Lyso GL-3 levels in Indian patients of GD and FD respectively. These results will be useful for early diagnosis to improve management of these LSDs.

The fatal fetal tumor: a geneticist's perspective.

Epignathus is an extremely rare oral teratoma which leads to high mortality in the early neonatal period. Various theories have been put forward for the genesis of such a tumor, though none is completely convincing. A genetic basis is not well established for the tumor. Microdeletions/duplications, as well as single gene disorders, have been known to cause epignathus, all with additional malformations. Evidence of single gene involvement in an isolated epignathus is lacking. We present a case of a 19-week-fetus with oro-pharyngeal teratoma detected on the level II ultrasound. The couple was counseled regarding the grave prognosis of the fetal condition following which they opted for termination of pregnancy and fetal autopsy. The autopsy revealed fetus-like body attached to the tumor. Genetic testing including a whole genome microarray did not reveal any significant variant. An explanation for the fetus-like body maybe a common origin of the teratoma and the additional fetus-like bodies due to an erroneous process of early embryonic development. Another possibility is of an acardiacus acranius twin masquerading as a fetus-like body. Thus, we conclude that in the absence of an associated malformation, an epignathus is unlikely to have a genetic etiology. This study highlights the importance of performing a fetal autopsy as a part of deep phenotyping to ascertain the etiology, as it identified additional fetal-like body which was not detected on the antenatal ultrasound.

Lysosomal storage disorders: Novel and frequent pathogenic variants in a large cohort of Indian patients of Pompe, Fabry, Gaucher and Hurler disease.

OBJECTIVES: Diagnosis of lysosomal storage disorders (LSDs) remains challenging due to wide clinical, biochemical and molecular heterogeneity. The study applies a combined biochemical and genetic approach to diagnose symptomatic Indian patients of Pompe, Fabry, Gaucher and Hurler disease to generate a comprehensive dataset of pathogenic variants for these disorders. DESIGN & METHODS: Symptomatic patients were biochemically diagnosed by fluorometric methods and molecular confirmation was carried out by gene sequencing. Genetic variants were analyzed according to the ACMG/AMP 2015 variant interpretation guidelines. RESULTS: Amongst the 2181 suspected patients, 285 (13%) were biochemically diagnosed. Of these, 22.5% (64/285) diagnosed with Pompe disease harboured c.1933G>A, c.1A>G, c.1927G>A and c.2783G>C as common and 10 novel pathogenic variants while 7.4% (21/285) patients diagnosed with Fabry disease carried c.851T>C, c.902G>A, c.905A>C and c.1212_1234del as frequent disease-causing variants along with 7 novel pathogenic variants. As many as 48.4% (138/285) patients were diagnosed with Gaucher disease and had c.1448T>C as the most common pathogenic variant followed by c.1342G>C and c.754T>C with 7 previously unreported disease-causing variants and in the 21.7% (62/285) diagnosed cases of Hurler disease, c.1469T>C, c.754delC c.568_581del and c.1898C>T were identified as the most common causative variants along with 21 novel pathogenic variants. CONCLUSION: This comprehensive data set of disease-causing frequent and novel pathogenic variants reported for the first time in such a large patient cohort for each of these four LSDs from the Indian sub-continent, along with their biochemical and clinical spectrum will contribute towards providing definitive diagnosis and treatment, identifying carrier status, as well as in counselling prenatal cases to reduce the morbidity and mortality associated with these disorders.

Prevalence of familial hypercholesterolemia in premature coronary artery disease patients admitted to a tertiary care hospital in North India.

AIMS: The prevalence of premature coronary artery disease (CAD) in India is two to three times more than other ethnic groups. Untreated heterozygous familial hypercholesterolemia (FH) is one of the important causes for premature CAD. As the age advances, these patients without treatment have 100 times increased risk of cardiovascular (CV) mortality resulting from myocardial infarction (MI). Recent evidence suggests that one in 250 individuals may be affected by FH (nearly 40 million people globally). It is indicated that the true global prevalence of FH is underestimated. The true prevalence of FH in India remains unknown. METHODS: A total of 635 patients with premature CAD were assessed for FH using the Dutch Lipid Clinical Network (DLCN) criteria. Based on scores, patients were diagnosed as definite, probable, possible, or no FH. Other CV risk factors known to cause CAD such as smoking, diabetes mellitus, and hypertension were also recorded. RESULTS: Of total 635 patients, 25 (4%) were diagnosed as definite, 70 (11%) as probable, 238 (37%) as possible, and 302 (48%) without FH, suggesting the prevalence of potential (definite + probable) FH of about 15% in the North Indian population. FH is more common in younger patients, and they have lesser incidence of common CV risk factors such as diabetes, hypertension, and smoking than the younger MI patients without FH (26.32% vs.42.59%; 17.89% vs.29.44%; 22.11% vs.40.74%). CONCLUSION: FH prevalence is high among patients with premature CAD admitted to a cardiac unit. To detect patients with FH, routine screening with simple criteria such as family history of premature CAD combined with hypercholesterolemia, and a DLCN criteria score >5 may be effectively used.

Autosomal Dominant Polycystic Kidney Disease: Presence of Hypomorphic Alleles in PKD1 Gene.

Autosomal dominant polycystic kidney disease is characterized by multiple cysts in both kidneys manifesting in adult life. In general, the disorder is caused by a pathogenic variant in one allele of PKD1 or PKD2 genes, while the other allele is normal. Pathogenic variants in both the alleles are rare and have variable phenotypes, from lethal or perinatal presentation to a mild form in later adulthood, depending on the type of variant. Here, we describe a proband with two variants (p.Thr1773Ile and p.Ala1871Thr in trans) in PKD1 gene, who presented with disease at age 24 years. Both the parents and one brother had a variant in one allele, the other being wild type only and had normal ultrasound findings. Segregation studies suggest that both the variants may act as "hypomorphic" or "incompletely penetrant" alleles and acting together resulted in haploinsufficiency of protein PC1 in renal cells, leading to cystogenesis in the proband. The consequences of the presence of two hypomorphic variants have been poorly documented in literature. We reviewed the few published cases having two hypomorphic variants and the data conform to the conclusions that we reached by study of the family described. It is emphasized that to resolve the significance of suspected hypomorphic variants, segregation studies in the parents and siblings are essential.

Sequencing of FIC1, BSEP and MDR3 in a large cohort of patients with cholestasis revealed a high number of different genetic variants.

BACKGROUND & AIMS: The bile salt export pump (BSEP, ABCB11), multidrug resistance protein 3 (MDR3, ABCB4) and the ATPase familial intrahepatic cholestasis 1 (FIC1, ATP8B1) mediate bile formation. This study aimed to determine the contribution of mutations and common variants in the FIC1, BSEP and MDR3 genes to cholestatic disorders of differing disease onset and severity. METHODS: Coding exons with flanking intron regions of ATP8B1, ABCB11, and ABCB4 were sequenced in cholestatic patients with assumed genetic cause. The effects of new variants were evaluated by bioinformatic tools and 3D protein modeling. RESULTS: In 427 patients with suspected inherited cholestasis, 149 patients carried at least one disease-causing mutation in FIC1, BSEP or MDR3, respectively. Overall, 154 different mutations were identified, of which 25 were novel. All 13 novel missense mutations were disease-causing according to bioinformatics analyses and homology modeling. Eighty-two percent of patients with at least one disease-causing mutation in either of the three genes were children. One or more common polymorphism(s) were found in FIC1 in 35.3%, BSEP in 64.3% and MDR3 in 72.6% of patients without disease-causing mutations in the respective gene. Minor allele frequencies of common polymorphisms in BSEP and MDR3 varied in our cohort compared to the general population, as described by gnomAD. However, differences in ethnic background may contribute to this effect. CONCLUSIONS: In a large cohort of patients, 154 different variants were detected in FIC1, BSEP, and MDR3, 25 of which were novel. In our cohort, frequencies for risk alleles of BSEP (p.V444A) and MDR3 (p.I237I) polymorphisms were significantly overrepresented in patients without disease-causing mutation in the respective gene, indicating that these common variants can contribute to a cholestatic phenotype. LAY SUMMARY: FIC1, BSEP, and MDR3 represent hepatobiliary transport proteins essential for bile formation. Genetic variants in these transporters underlie a broad spectrum of cholestatic liver diseases. To confirm a genetic contribution to the patients' phenotypes, gene sequencing of these three major cholestasis-related genes was performed in 427 patients and revealed 154 different variants of which 25 have not been previously reported in a database. In patients without a disease-causing mutation, common genetic variants were detected in a high number of cases, indicating that these common variants may contribute to cholestasis development.

Infantile Systemic Hyalinosis: Novel Founder Mutation in the Initiation Codon among "Malis (Farmers)" in Jodhpur.

Infantile systemic hyalinosis (OMIM 236490) is a progressive autosomal recessive disorder characterized by widespread deposition of hyaline material in many tissues leading to multiple subcutaneous skin nodules, gingival hypertrophy and joint contractures. The authors describe five children from four unrelated families, from the "mali (farmer)" community in Jodhpur, with the disorder. All of them had classical clinical features, and four died from severe infections between age of 7 mo to 3 y. Two affected children had the same, but novel mutation in the initiation codon, in homozygous form c.1 A > G; p. M1? in capillary morphogenesis protein-2 (CMG2), or ANTXR2 gene on chromosome 4q21.21. The other two parents had the same mutation in heterozygous form. It is likely that this is a founder mutation in this community.

Fanconi-Bickel syndrome - mutation in SLC2A2 gene.

Fanconi-Bickel Syndrome (FBS) is a rare autosomal recessive disorder of carbohydrate metabolism. The defect in the GLUT 2 receptors in the hepatocytes, pancreas and renal tubules leads to symptoms secondary to glycogen storage, glucose metabolism and renal tubular dysfunction. Derangement in glucose metabolism is classical with fasting hypoglycemia and post-prandial hyperglycemia. The authors report a 4-year-old boy who presented with failure to thrive, motor delay, protuberant abdomen and was noted to have huge hepatomegaly with glycogen deposition in liver, and renal tubular acidosis. Gene sequencing revealed homozygous mutation, c.1330T > C in SLC2A2 gene, thus confirming the diagnosis of FBS. Only three mutations have been reported from India so far. The primary reason for referral to authors' hospital was for liver transplantation, but an accurate diagnosis led to avoidance of the major surgery and streamlining of treatment with clinical benefit to the child and family.

Primary immunodeficiency disorders in the developing world: data from a hospital-based registry in India.

Primary immunodeficiency disorders (PID) are under-reported from the developing world. We present data regarding diagnosis and outcome from a hospital-based registry in India. Forty-seven patients fulfilled diagnostic criteria. Majority were males. Subgroups were disorders of immune dysregulation-29%, B&T-cell abnormalities-28%, predominant antibody deficiencies-23%, other well-defined immunodeficiencies-15%, and phagocyte disorders-4%. Molecular diagnosis was attempted in 12 and was positive in seven. Overall 24 children died. Only three out of 28 children needing stem cell transplant (SCT) underwent the same. Registry data highlights that molecular diagnosis and SCT are a rarity for children with PIDs in the developing world and mortality is high.

Prevalence of CYP2C8 polymorphisms in a North Indian population.

CYP2C8 is an important member of the cytochrome P450 family of enzymes; it affects the activity of various drugs used in routine clinical practice, including amiodarone, chloroquine, amodiaquine, and repaglinide, as well as endogenous compounds, such as arachidonic acid and retonic acid. It is also the main enzyme involved in the metabolism of the widely used anticancer drug Paclitaxel, which has a very narrow therapeutic index. There is evidence that single nucleotide polymorphisms in the CYP2C8 gene influence the adverse reactions and/or the efficacy of drugs metabolized by this enzyme. We examined the allele and genotype frequencies of widely studied functional polymorphisms of the CYP2C8 gene in a North Indian population. We assayed the genomic DNA of at least 251 healthy unrelated North Indians for CYP2C8*2, CYP2C8*3 (G416A, A1196G), and CYP2C8*4 genetic polymorphisms by RFLP technique. These results were compared to information on other populations. The allelic frequencies of CYP2C8*2, CYP2C8*3, and CYP2C8*4 were found to be 3, 4, and 4% respectively. The two CYP2C8*3 polymorphisms (G416A and A1196G) were found to be completely linked to each other. Allele frequencies of CYP2C8 genetic variants in northern Indians were found to have a distinct pattern that differs from that of southern Indian and other global populations. This is the first report from North India on CYP2C8 polymorphisms. Ethnic differences with respect to polymorphisms are the molecular basis of interethnic variability in pharmacokinetics. Our study may help in rational use of drugs that are substrates for CYP2C8 in this population.

Trichohepatoenteric syndrome: founder mutation in asian indians.

Trichohepatoenteric syndrome (THES) is characterized by chronic diarrhea, dysmorphic facies and hair abnormalities. Hepatic involvement varies from no abnormality to cirrhosis and hemochromatosis. Recently, mutations in the tetratricopeptide repeat domain 37 (TTC37) gene were identified to cause THES. The c.2808G>A variation was suggested as a possible founder mutation among the South Asians. We further report 2 unrelated cases of Asian-Indian ethnicity (Gujrati) with THES, wherein targeted mutation analysis revealed the same mutation in homozygous form in both cases. These findings, as well as haplotype analysis, corroborate the founder mutation hypothesis amongst Asian Indo-Pakistani ethnic groups. A restriction enzyme-based method is also described to identify this founder mutation. One of our probands had multiple hepatic hemangiomas, a feature not previously observed in this syndrome.

Premature coronary artery disease and familial hypercholesterolemia: need for early diagnosis and cascade screening in the Indian population.

Cardiovascular disease (CVD) is the leading cause of death in India, accounting for 28% of mortality. The average age of onset of CVD is younger (below 55 years) among Indians than in other populations. This may be due to bad lifestyle, genetic factors, or both. Hypertension, smoking, diabetes, and physical inactivity have been identified as modifiable risk factors for heart disease. Hypercholesterolemia is the most common and treatable cause of heart disease. Genetic factors that lead to hypercholesterolemia have not been fully studied in India. Familial Hypercholesterolemia results from mutations in the LDL receptor, ApoB, PCSK9, and ApoE genes. There is an urgent need to screen subjects with premature CAD and their relatives in India for the presence of FH, identify the mutations that lead to high cholesterol, and carry out cascade screening in the at-risk relatives. Those harbouring mutations in the above genes can be treated to lower the cholesterol levels, prevent early CVD, and avoid death. A programme based on these lines has been initiated in Delhi.

Recombinant macrophage targeted enzyme replacement therapy for Gaucher disease in India.

OBJECTIVE: Gaucher disease in India has been reported only in a few case reports from India. The aim of the study was to assess the response to enzyme replacement therapy in Indian patients with Gaucher disease. DESIGN: Retrospective analysis of patients receiving CHO-derived recombinant macrophage-targetted glucocorebrosidase. SETTING: Five centers from India with experience in treating lysosomal storage disorders. PATIENTS: The diagnosis of Gaucher disease was confirmed by low glucocerebrosidase levels, though it was first made on splenectomy in 8 and on bone marrow examination in 9 patients. Twenty five of 52 patients diagnosed with Gaucher disease (17 Type I, 8 mild Type III) received treatment for >6 months. Indications for treatment included symptomatic anemia, thrombo-cytopenia, organomegaly, bone disease or mild neurological symptoms leading to impairment of quality of life. Patients with significant neurological involvement were excluded. The drug infusions were given intravenously every 15 days. MAIN OUTCOME MEASURES: Hemoglobin, platelet counts, liver and spleen volumes and growth parameters. RESULTS: 22 of the 25 children who survived were analyzed. After 6 months of treatment, the mean (range) increase in hemoglobin was 1.5 (-3.4 to 6.1) g/dL (P=0.01) and in platelet count was 32 x 10(9)/L (-98.5 x 109 to 145.5 x10(9))/L (P=0.02). The mean (range) increase in weight was 3 kg (-5.6 to 10.5) (P=0.04) and in height was 7.1 cm (0 to 26.5) (P=0.0003). Liver size decreased by a mean (range) of 38.5% (- 5.5 to 86.7) (P=0.0003) and the spleen size by 34.8% (0 to 91.7) (P=0.004). All patients had improvement in bone pains and in 2 patients, neurological symptoms improved with others remaining static. CONCLUSIONS: This is the first reported cohort of patients in India reporting our experience with imiglucerase enzyme replacement therapy for treatment of Gaucher Disease in India.

Congenital hyperinsulinism caused by mutations in ABCC8 (SUR1) gene.

Congenital hyperinsulinism is the most frequent cause of severe, persistent hypoglycemia in infancy and childhood. We report a 2.5 year old girl with severe congenital hyperinsulinism. Mutation analysis showed that the child is a compound heterozygote for two missense mutations in the ABCC8 gene.

Mutation studies in X-linked myotubular myopathy in three Indian families.

Congenital myopathies are a group of genetic disorders characterized by generalised muscle hypotonia and weakness of varying severity. They are distinct entities and do not include muscular dystrophies, metabolic myopathies and mitochondrial disorders. Myotubular myopathy is a rare sub type within this group of disorders. Clinical differentiation of the various types is difficult and requires muscle biopsy with histopathological and immunohistochemical studies for specific diagnosis. Gene studies are a prerequisite for genetic counseling adn prenatal diagnosis. Here presented three cases of X-linked myotubular myopathy in three Indian families where the diagnosis was established by mutation analysis in the MTM1 gene in all, and supported his histopathology in two. All three families had history of previous male neonatal deaths with similar complaints. Molecular analysis revealed hemizygous mutations in the MTM1 gene including c.1261-10A>G in case, 1, c.70C>T (R24X) in case 2, and a previously unreported mutation, c.924_926delCTT(p. F308del), in case 3. Genetic counseling was performed regarding the X-linked inheritance, their 50% risk of recurrence in boys in subsequent pregnancies, and a feasibility of prenatal diagnosis. This is the first report of cases of X-linked myotubular myopathy from India.

Spectrum of severe skeletal dysplasias in North India.

OBJECTIVE: Severe skeletal dysplasias are a group of bone growth disorders characterized by a lethal outcome in utero or infancy. We describe our experience of the severe skeletal dysplasias diagnosed amongst fetal autopsies done at a tertiary level centre over a five year period. METHODS: We evaluated 15 cases with short limbed dwarfism, of which 13 fetuses were examined after termination of pregnancy and two were evaluated postnatally. RESULTS: Short rib dysplasia syndromes with or without polydactyly, osteogenesis imperfecta type II, thanatophoric dysplasia, campomelic dysplasia, chondrodysplasia punctata, rhizomelic type and achondrogenesis were the lethal skeletal dysplasias diagnosed. CONCLUSION: Precise identification of the tye of skeletal dysplasia is paramount for proper genetic counseling. Postnatal examination and detailed radiographic examination of the fetus especially of the pelvis, limbs, skull and spine are essential to identify the type of skeletal dysplasia.

Genetic counseling and prenatal diagnosis in India--experience at Sir Ganga Ram Hospital.

UNLABELLED: The experiences in genetic counseling and prenatal diagnosis at a tertiary genetic center in India are described. Of 3500 subjects provided genetic counseling 28.7% were for prenatal diagnosis, 13.7% for mental retardation +/- malformations, 11.5% for thalassemia, hemophilia and leukemia, 8.5% for neural tube defects and other malformations, and 8% for muscle dystrophy and spinal muscle atrophy. Chromosomal studies in blood (n = 5459) were for recurrent abortions (57.8%), delayed milestones (14.7%), malformations (11%), and infertility and amenorrhea (10.2%). Indications for amniotic fluid studies (n = 835) were advanced maternal age (35.7%), high risk result on triple test (21.3%), previous child with trisomy 21 (21.3%) and abnormalities seen on ultrasound (11.1%). Molecular studies were mostly for thalassemia (843, 24.3%), Duchenne muscular dystrophy (443, 12.5%), fragile X syndrome (367, 10.3%), spinal muscular atrophy (315, 8.9%), thrombophilia profile (233, 6.6%), triplet repeat disorders-spinocerebellar ataxias, Huntington disease and Friedreich ataxia-162 (4.6%), cystic fibrosis 140 (3.9%) and mitochondrial disorders 101 (2.9%). Other disorders for which molecular diagnosis was done were intrauterine infections by PCR on the amniotic fluid, Prader Willi/Angelman syndromes, hemophilia, achondroplasia, congenital adrenal hyperplasia, and Apert syndrome etc. In biochemical studies triple marker tests were the most common (3239), followed by aminoacid chromatography (774). Among neurolipidosis metachromatic leukodystrophy was the commonest, followed by Krabbe's disease, Tay Sach disease and Gaucher disease. Of the mucopolysacharidoses Hurler syndrome was the commonest, followed by Hunter syndrome. These data are compared with previous studies and a change towards increased prenatal diagnostic tests is observed. The commonest indication for amniocentesis has changed to advanced maternal age. CONCLUSION: Advanced molecular, cytogenetic and biochemical techniques have been a useful addition for genetic counseling and prenatal diagnosis in India.