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1.  Recurrent ACADVL molecular findings in individuals with a positive newborn screen for very long chain acyl-coA dehydrogenase (VLCAD) deficiency in the United States 
Molecular genetics and metabolism  2015;116(3):139-145.
Very long chain acyl-coA dehydrogenase deficiency (VLCADD) is an autosomal recessive inborn error of fatty acid oxidation detected by newborn screening (NBS). Follow-up molecular analyses are often required to clarify VLCADD-suggestive NBS results, but to date the outcome of these studies are not well described for the general screen-positive population. In the following study, we report the molecular findings for 693 unrelated patients that sequentially received Sanger sequence analysis of ACADVL as a result of a positive NBS for VLCADD. Highlighting the variable molecular underpinnings of this disorder, we identified 94 different pathogenic ACADVL variants (40 novel), as well as 134 variants of unknown clinical significance (VUSs). Evidence for the pathogenicity of a subset of recurrent VUSs was provided using multiple in silico analyses. Surprisingly, the most frequent finding in our cohort was carrier status, 57% all individuals had a single pathogenic variant or VUS. This result was further supported by follow-up array and/or acylcarnitine analysis that failed to provide evidence of a second pathogenic allele. Notably, exon-targeted array analysis of 131 individuals screen positive for VLCADD failed to identify copy number changes in ACADVL thus suggesting this test has a low yield in the setting of NBS follow-up. While no genotype was common, the c.848T>C (p.V283A) pathogenic variant was clearly the most frequent; at least one copy was found in ∼10% of all individuals with a positive NBS. Clinical and biochemical data for seven unrelated patients homozygous for the p.V283A allele suggests that it results in a mild phenotype that responds well to standard treatment, but hypoglycemia can occur. Collectively, our data illustrate the molecular heterogeneity of VLCADD and provide novel insight into the outcomes of NBS for this disorder.
doi:10.1016/j.ymgme.2015.08.011
PMCID: PMC4790081  PMID: 26385305
VLCAD; inborn error of metabolism; fatty acid oxidation; newborn screening; ACADVL; VLCADD; NBS; V283A; V243A
2.  High Incidence of Noonan Syndrome Features Including Short Stature and Pulmonic Stenosis in Patients carrying NF1 Missense Mutations Affecting p.Arg1809: Genotype–Phenotype Correlation 
Rojnueangnit, Kitiwan | Xie, Jing | Gomes, Alicia | Sharp, Angela | Callens, Tom | Chen, Yunjia | Liu, Ying | Cochran, Meagan | Abbott, Mary‐Alice | Atkin, Joan | Babovic‐Vuksanovic, Dusica | Barnett, Christopher P. | Crenshaw, Melissa | Bartholomew, Dennis W. | Basel, Lina | Bellus, Gary | Ben‐Shachar, Shay | Bialer, Martin G. | Bick, David | Blumberg, Bruce | Cortes, Fanny | David, Karen L. | Destree, Anne | Duat‐Rodriguez, Anna | Earl, Dawn | Escobar, Luis | Eswara, Marthanda | Ezquieta, Begona | Frayling, Ian M. | Frydman, Moshe | Gardner, Kathy | Gripp, Karen W. | Hernández‐Chico, Concepcion | Heyrman, Kurt | Ibrahim, Jennifer | Janssens, Sandra | Keena, Beth A | Llano‐Rivas, Isabel | Leppig, Kathy | McDonald, Marie | Misra, Vinod K. | Mulbury, Jennifer | Narayanan, Vinodh | Orenstein, Naama | Galvin‐Parton, Patricia | Pedro, Helio | Pivnick, Eniko K. | Powell, Cynthia M. | Randolph, Linda | Raskin, Salmo | Rosell, Jordi | Rubin, Karol | Seashore, Margretta | Schaaf, Christian P. | Scheuerle, Angela | Schultz, Meredith | Schorry, Elizabeth | Schnur, Rhonda | Siqveland, Elizabeth | Tkachuk, Amanda | Tonsgard, James | Upadhyaya, Meena | Verma, Ishwar C. | Wallace, Stephanie | Williams, Charles | Zackai, Elaine | Zonana, Jonathan | Lazaro, Conxi | Claes, Kathleen | Korf, Bruce | Martin, Yolanda | Legius, Eric | Messiaen, Ludwine
Human Mutation  2015;36(11):1052-1063.
ABSTRACT
Neurofibromatosis type 1 (NF1) is one of the most frequent genetic disorders, affecting 1:3,000 worldwide. Identification of genotype–phenotype correlations is challenging because of the wide range clinical variability, the progressive nature of the disorder, and extreme diversity of the mutational spectrum. We report 136 individuals with a distinct phenotype carrying one of five different NF1 missense mutations affecting p.Arg1809. Patients presented with multiple café‐au‐lait macules (CALM) with or without freckling and Lisch nodules, but no externally visible plexiform neurofibromas or clear cutaneous neurofibromas were found. About 25% of the individuals had Noonan‐like features. Pulmonic stenosis and short stature were significantly more prevalent compared with classic cohorts (P < 0.0001). Developmental delays and/or learning disabilities were reported in over 50% of patients. Melanocytes cultured from a CALM in a segmental NF1‐patient showed two different somatic NF1 mutations, p.Arg1809Cys and a multi‐exon deletion, providing genetic evidence that p.Arg1809Cys is a loss‐of‐function mutation in the melanocytes and causes a pigmentary phenotype. Constitutional missense mutations at p.Arg1809 affect 1.23% of unrelated NF1 probands in the UAB cohort, therefore this specific NF1 genotype–phenotype correlation will affect counseling and management of a significant number of patients.
doi:10.1002/humu.22832
PMCID: PMC5049609  PMID: 26178382
neurofibromatosis type 1; NF1; p.Arg1809; phenotype–genotype correlations; Legius syndrome
3.  EFTUD2 deficiency in vertebrates: identification of a novel human mutation and generation of a zebrafish model 
Background
Congenital microphthalmia and coloboma are severe developmental defects that are frequently associated with additional systemic anomalies and display a high level of genetic heterogeneity.
Methods
To identify the pathogenic variant in a patient with microphthalmia, coloboma, retinal dystrophy, microcephaly and other features, whole exome sequencing (WES) analysis of the patient and parental samples was undertaken. To further explore the identified variant/gene, expression and functional studies in zebrafish were performed.
Results
WES revealed a de novo variant, c.473_474delGA, p.(Arg158Lysfs*4), in EFTUD2 which encodes a component of the spliceosome complex. Dominant mutations in EFTUD2 cause Mandibulofacial Dysostosis, Guion-Almeida type (MFDGA) which does not involve microphthalmia, coloboma or retinal dystrophy; analysis of genes known to cause these ocular phenotypes identified several variants of unknown significance but no causal alleles in the affected patient. Zebrafish eftud2 demonstrated high sequence conservation with the human gene and broad embryonic expression. TALEN-mediated disruption was employed to generate a c.378_385 del, p.(Ser127Aspfs*23) truncation mutation in eftud2. Homozygous mutants displayed a reduced head size, small eye, curved body, and early embryonic lethality. Apoptosis assays demonstrated a striking increase in TUNEL-positive cells in the developing brain, eye, spinal cord and other tissues starting at 30 hours post fertilization.
Conclusion
This study reports a novel mutation in EFTUD2 in an MFDGA patient with unusual ocular features and the generation of a first animal model of eftud2 deficiency. The severe embryonic phenotype observed in eftud2 mutants indicates an important conserved role during development of diverse tissues in vertebrates.
doi:10.1002/bdra.23397
PMCID: PMC4487781  PMID: 26118977
EFTUD2; coloboma; retinal dystrophy; microphthalmia; zebrafish
4.  Whole exome analysis identifies dominant COL4A1 mutations in patients with complex ocular phenotypes involving microphthalmia 
Clinical genetics  2014;86(5):475-481.
Anophthalmia/microphthalmia (A/M) is a developmental ocular malformation defined as complete absence or reduction in size of the eye. A/M is a heterogeneous disorder with numerous causative genes identified; however, about half the cases lack a molecular diagnosis. We undertook whole exome sequencing in an A/M family with two affected siblings, two unaffected siblings, and unaffected parents; the ocular phenotype was isolated with only mild developmental delay/learning difficulties reported and a normal brain MRI in the proband at 16 months. No pathogenic mutations were identified in 71 known A/M genes. Further analysis identified a shared heterozygous mutation in COL4A1, c.2317G>A, p.(Gly773Arg) that was not seen in the unaffected parents and siblings. Analysis of twenty-four unrelated A/M exomes identified a novel c.2122G>A, p.(Gly708Arg) mutation in an additional patient with unilateral microphthalmia, bilateral microcornea, glaucoma and Peters anomaly; the mutation was absent in the unaffected mother and the unaffected father was not available. Mutations in COL4A1 have been linked to a spectrum of human disorders; the most consistent feature is cerebrovascular disease with variable ocular anomalies, kidney and muscle defects. This study expands the spectrum of COL4A1 phenotypes and indicates screening in patients with A/M regardless of MRI findings or presumed inheritance pattern.
doi:10.1111/cge.12379
PMCID: PMC4163542  PMID: 24628545
microphthalmia; Peters anomaly; whole exome sequencing; COL4A1; small vessel disease; stroke
5.  Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology 
The American College of Medical Genetics and Genomics (ACMG) previously developed guidance for the interpretation of sequence variants.1 In the past decade, sequencing technology has evolved rapidly with the advent of high-throughput next generation sequencing. By adopting and leveraging next generation sequencing, clinical laboratories are now performing an ever increasing catalogue of genetic testing spanning genotyping, single genes, gene panels, exomes, genomes, transcriptomes and epigenetic assays for genetic disorders. By virtue of increased complexity, this paradigm shift in genetic testing has been accompanied by new challenges in sequence interpretation. In this context, the ACMG convened a workgroup in 2013 comprised of representatives from the ACMG, the Association for Molecular Pathology (AMP) and the College of American Pathologists (CAP) to revisit and revise the standards and guidelines for the interpretation of sequence variants. The group consisted of clinical laboratory directors and clinicians. This report represents expert opinion of the workgroup with input from ACMG, AMP and CAP stakeholders. These recommendations primarily apply to the breadth of genetic tests used in clinical laboratories including genotyping, single genes, panels, exomes and genomes. This report recommends the use of specific standard terminology: ‘pathogenic’, ‘likely pathogenic’, ‘uncertain significance’, ‘likely benign’, and ‘benign’ to describe variants identified in Mendelian disorders. Moreover, this recommendation describes a process for classification of variants into these five categories based on criteria using typical types of variant evidence (e.g. population data, computational data, functional data, segregation data, etc.). Because of the increased complexity of analysis and interpretation of clinical genetic testing described in this report, the ACMG strongly recommends that clinical molecular genetic testing should be performed in a CLIA-approved laboratory with results interpreted by a board-certified clinical molecular geneticist or molecular genetic pathologist or equivalent.
doi:10.1038/gim.2015.30
PMCID: PMC4544753  PMID: 25741868
clinical genetic testing; ACMG laboratory guideline; sequence variation; variant terminology; interpretation; reporting
6.  Novel B3GALTL mutations in classic Peters Plus syndrome and lack of mutations in a large cohort of patients with similar phenotypes 
Clinical genetics  2013;86(2):142-148.
Peters Plus syndrome (PPS) is a rare autosomal-recessive disorder characterized by Peters anomaly of the eye, short stature, brachydactyly, dysmorphic facial features, developmental delay, and variable other systemic abnormalities. In this report we describe screening of 64 patients affected with PPS, isolated Peters anomaly and PPS-like phenotypes. Mutations in the coding region of B3GALTL were identified in nine patients; six had a documented phenotype of classic PPS and the remaining three had a clinical diagnosis of PPS with incomplete clinical documentation. A total of nine different pathogenic alleles were identified. Five alleles are novel including one frameshift, c.168dupA, p.(Gly57Argfs*11), one nonsense, c.1234C>T, p.(Arg412*), two missense, c.1045G>A, p.(Asp349Asn) and c.1181G>A, p.(Gly394Glu), and one splicing, c.347+5G>T, mutations. Consistent with previous reports, the c.660+1G>A mutation was the most common mutation identified, seen in eight of the nine patients and accounting for 55% of pathogenic alleles in this study and 69% of all reported pathogenic alleles; while two patients were homozygous for this mutation, the majority had a second rare pathogenic allele. We also report the absence of B3GALTL mutations in 55 cases of PPS-like phenotypes or isolated Peters anomaly, further establishing the strong association of B3GALTL mutations with classic PPS only.
doi:10.1111/cge.12241
PMCID: PMC4103962  PMID: 23889335
7.  Leiomodin-3 dysfunction results in thin filament disorganization and nemaline myopathy 
The Journal of Clinical Investigation  2014;124(11):4693-4708.
Nemaline myopathy (NM) is a genetic muscle disorder characterized by muscle dysfunction and electron-dense protein accumulations (nemaline bodies) in myofibers. Pathogenic mutations have been described in 9 genes to date, but the genetic basis remains unknown in many cases. Here, using an approach that combined whole-exome sequencing (WES) and Sanger sequencing, we identified homozygous or compound heterozygous variants in LMOD3 in 21 patients from 14 families with severe, usually lethal, NM. LMOD3 encodes leiomodin-3 (LMOD3), a 65-kDa protein expressed in skeletal and cardiac muscle. LMOD3 was expressed from early stages of muscle differentiation; localized to actin thin filaments, with enrichment near the pointed ends; and had strong actin filament-nucleating activity. Loss of LMOD3 in patient muscle resulted in shortening and disorganization of thin filaments. Knockdown of lmod3 in zebrafish replicated NM-associated functional and pathological phenotypes. Together, these findings indicate that mutations in the gene encoding LMOD3 underlie congenital myopathy and demonstrate that LMOD3 is essential for the organization of sarcomeric thin filaments in skeletal muscle.
doi:10.1172/JCI75199
PMCID: PMC4347224  PMID: 25250574
10.  Nasal Embryonic LHRH Factor (NELF) Mutations in Patients with Normosmic Hypogonadotropic Hypogonadism and Kallmann Syndrome 
Fertility and sterility  2011;95(5):1613-20.e1-7.
Study Objective
To determine if mutations in NELF, a gene isolated from migratory GnRH neurons, cause normosmic idiopathic hypogonadotropic hypogonadism (IHH) and Kallmann syndrome (KS)
Design
Molecular analysis correlated with phenotype
Setting
Academic medical center
Patients
168 IHH/KS patients along with unrelated controls were studied for NELF mutations.
Intervention
NELF coding regions/splice junctions were subjected to PCR-based DNA sequencing, Eleven additional IHH/KS genes were sequenced in three patients with NELF mutations.
Main Outcome Measure
Mutations were confirmed by SIFT, RT-PCR, and western blot analysis.
Results
Three novel NELF mutations absent in 372-ethnically matched controls were identified in 3/168(1.8%) IHH/KS patients. One IHH patient had compound heterozygous NELF mutations (c.629-21C>G and c.629-23G>C); and he did not have mutations in 11 other known IHH/KS genes. Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of TACR3). In vitro evidence of these NELF mutations included reduced protein expression and splicing defects.
Conclusions
Our findings suggest that NELF is associated with normosmic IHH and KS, either singly or in combination with a mutation in another gene.
doi:10.1016/j.fertnstert.2011.01.010
PMCID: PMC3888818  PMID: 21300340
Nasal embryonic LHRH factor; hypogonadotropic hypogonadism; Kallmann syndrome; gonadotropin-releasing hormone (GnRH); GnRH neuron migration
12.  The prevalence of digenic mutations in patients with normosmic hypogonadotropic hypogonadism and Kallmann syndrome 
Fertility and sterility  2011;96(6):1424-1430.e6.
Objective
To determine the prevalence of digenic mutations in patients with idiopathic hypogonadotropic hypogonadism (IHH) and Kallmann syndrome (KS).
Design
Molecular analysis of DNA in IHH/KS patients.
Setting
Academic medical center.
Patient(s)
Twenty-four IHH/KS patients with a known mutation (group 1) and 24 IHH/KS patients with no known mutation (group 2).
Intervention(s)
DNA from IHH/KS patients was subjected to polymerase chain reaction–based DNA sequencing of the 13 most common genes (KAL1, GNRHR, FGFR1, KISS1R, TAC3, TACR3, FGF8, PROKR2, PROK2, CHD7, NELF, GNRH1, and WDR11).
Main Outcome Measure(s)
The identification of mutations absent in ≥188 ethnically matched controls. Both SIFT (sorting intolerant from tolerant) and conservation among orthologs provided supportive evidence for pathologic roles.
Result(s)
In group 1, 6 (25%) of 24 IHH/KS patients had a heterozygous mutation in a second gene, and in group 2, 13 (54.2%) of 24 had a mutation in at least one gene, but none had digenic mutations. In group 2, 7 (29.2%) of 24 had a mutation considered sufficient to cause the phenotype.
Conclusion(s)
When the 13 most common IHH/KS genes are studied, the overall prevalence of digenic gene mutations in IHH/KS was 12.5%. In addition, approximately 30% of patients without a known mutation had a mutation in a single gene. With the current state of knowledge, these findings suggest that most IHH/KS patients have a monogenic etiology.
doi:10.1016/j.fertnstert.2011.09.046
PMCID: PMC3573697  PMID: 22035731
Digenic mutations; idiopathic hypogonadotropic hypogonadism; Kallmann syndrome
14.  A Mosaic Activating Mutation in AKT1 Associated with the Proteus Syndrome 
The New England journal of medicine  2011;365(7):611-619.
BACKGROUND
The Proteus syndrome is characterized by the overgrowth of skin, connective tissue, brain, and other tissues. It has been hypothesized that the syndrome is caused by somatic mosaicism for a mutation that is lethal in the nonmosaic state.
METHODS
We performed exome sequencing of DNA from biopsy samples obtained from patients with the Proteus syndrome and compared the resultant DNA sequences with those of unaffected tissues obtained from the same patients. We confirmed and extended an observed association, using a custom restriction-enzyme assay to analyze the DNA in 158 samples from 29 patients with the Proteus syndrome. We then assayed activation of the AKT protein in affected tissues, using phosphorylation-specific antibodies on Western blots.
RESULTS
Of 29 patients with the Proteus syndrome, 26 had a somatic activating mutation (c.49G→A, p.Glu17Lys) in the oncogene AKT1, encoding the AKT1 kinase, an enzyme known to mediate processes such as cell proliferation and apoptosis. Tissues and cell lines from patients with the Proteus syndrome harbored admixtures of mutant alleles that ranged from 1% to approximately 50%. Mutant cell lines showed greater AKT phosphorylation than did control cell lines. A pair of single-cell clones that were established from the same starting culture and differed with respect to their mutation status had different levels of AKT phosphorylation.
CONCLUSIONS
The Proteus syndrome is caused by a somatic activating mutation in AKT1, proving the hypothesis of somatic mosaicism and implicating activation of the PI3K–AKT pathway in the characteristic clinical findings of overgrowth and tumor susceptibility in this disorder. (Funded by the Intramural Research Program of the National Human Genome Research Institute.)
doi:10.1056/NEJMoa1104017
PMCID: PMC3170413  PMID: 21793738
15.  Birth of a healthy infant following preimplantation PKHD1 haplotyping for autosomal recessive polycystic kidney disease using multiple displacement amplification 
Purpose
To develop a reliable preimplantation genetic diagnosis protocol for couples who both carry a mutant PKHD1 gene wishing to conceive children unaffected with autosomal recessive polycystic kidney disease (ARPKD).
Methods
Development of a unique protocol for preimplantation genetic testing using whole genome amplification of single blastomeres by multiple displacement amplification (MDA), and haplotype analysis with novel short tandem repeat (STR) markers from the PKHD1 gene and flanking sequences, and a case report of successful utilization of the protocol followed by successful IVF resulting in the birth of an infant unaffected with ARPKD.
Results
We have developed 20 polymorphic STR markers suitable for linkage analysis of ARPKD. These linked STR markers have enabled unambiguous identification of the PKHD1 haplotypes of embryos produced by at-risk couples.
Conclusions
We have developed a reliable protocol for preimplantation genetic diagnosis of ARPKD using single-cell MDA products for PKHD1 haplotyping.
doi:10.1007/s10815-010-9432-5
PMCID: PMC2922704  PMID: 20490649
Preimplantation genetic diagnosis; Autosomal recessive polycystic kidney disease; Multiple displacement amplification; PKHD1 haplotype analysis; Linkage analysis with linked STR markers
16.  Zoom‐in comparative genomic hybridisation arrays for the characterisation of variable breakpoint contiguous gene syndromes 
Journal of Medical Genetics  2007;44(1):e59.
Contiguous gene syndromes cause disorders via haploinsufficiency for adjacent genes. Some contiguous gene syndromes (CGS) have stereotypical breakpoints, but others have variable breakpoints. In CGS that have variable breakpoints, the extent of the deletions may be correlated with severity. The Greig cephalopolysyndactyly contiguous gene syndrome (GCPS‐CGS) is a multiple malformation syndrome caused by haploinsufficiency of GLI3 and adjacent genes. In addition, non‐CGS GCPS can be caused by deletions or duplications in GLI3. Although fluorescence in situ hybridisation (FISH) can identify large deletion mutations in patients with GCPS or GCPS‐CGS, it is not practical for identification of small intragenic deletions or insertions, and it is difficult to accurately characterise the extent of the large deletions using this technique. We have designed a custom comparative genomic hybridisation (CGH) array that allows identification of deletions and duplications at kilobase resolution in the vicinity of GLI3. The array averages one probe every 730 bp for a total of about 14 000 probes over 10 Mb. We have analysed 16 individuals with known or suspected deletions or duplications. In 15 of 16 individuals (14 deletions and 1 duplication), the array confirmed the prior results. In the remaining patient, the normal CGH array result was correct, and the prior assessment was a false positive quantitative polymerase chain reaction result. We conclude that high‐density CGH array analysis is more sensitive than FISH analysis for detecting deletions and provides clinically useful results on the extent of the deletion. We suggest that high‐density CGH array analysis should replace FISH analysis for assessment of deletions and duplications in patients with contiguous gene syndromes caused by variable deletions.
doi:10.1136/jmg.2006.042473
PMCID: PMC2597909  PMID: 17098889
GLI3 ; oligonucleotide array; comparative genomic hybridization
17.  Preimplantation HLA haplotyping using tri-, tetra-, and pentanucleotide short tandem repeats for HLA matching 
Purpose
To aid couples wishing to conceive children who are HLA matched to a sibling in need of a hematopoietic progenitor cell transplant, we developed a preimplantation HLA haplotype analysis of embryos that utilizes tri-, tetra-, and pentanucleotide STR markers.
Methods
For preimplantation HLA genotyping, we use polymorphic STR markers located across the HLA and flanking regions, selecting exclusively tri-, tetra-, and pentanucleotide repeats. These markers can be resolved using either capillary electrophoresis (CE) or polyacrylamide gels.
Results
We have developed 43 reliable STR markers for preimplantation HLA matching. Selected STR markers enabled unambiguous identification of embryos whose HLA haplotypes were matched with the affected patient using polyacrylamide gel or capillary electrophoresis.
Conclusions
The use of tri-, tetra-, and pentanucleotide repeat markers and polyacrylamide gels for STR genotyping in HLA matching is a simple and cost effective approach to clinical testing.
Electronic supplementary material
The online version of this article (doi:10.1007/s10815-008-9233-2) contains supplementary material, which is available to authorized users.
doi:10.1007/s10815-008-9233-2
PMCID: PMC2596682  PMID: 18677557
Haplotype analysis; Preimplantation genetic diagnosis; Preimplantation HLA matching; Short tandem repeats; Human leukocyte antigen
18.  The prevalence of intragenic deletions in patients with idiopathic hypogonadotropic hypogonadism and Kallmann syndrome 
Molecular Human Reproduction  2008;14(6):367-370.
Idiopathic hypogonadotropic hypogonadism (IHH) and Kallmann syndrome (KS) are clinically and genetically heterogeneous disorders caused by a deficiency of gonadotrophin-releasing hormone (GnRH). Mutations in three genes—KAL1, GNRHR and FGFR1—account for 15–20% of all causes of IHH/KS. Nearly all mutations are point mutations identified by traditional PCR-based DNA sequencing. The relatively new method of multiplex ligation-dependent probe amplification (MLPA) has been successful for detecting intragenic deletions in other genetic diseases. We hypothesized that MLPA would detect intragenic deletions in ∼15–20% of our cohort of IHH/KS patients. Fifty-four IHH/KS patients were studied for KAL1 deletions and 100 were studied for an autosomal panel of FGFR1, GNRH1, GNRHR, GPR54 and NELF gene deletions. Of all male and female subjects screened, 4/54 (7.4%) had KAL1 deletions. If only anosmic males were considered, 4/33 (12.1%) had KAL1 deletions. No deletions were identified in any of the autosomal genes in 100 IHH/KS patients. We believe this to be the first study to use MLPA to identify intragenic deletions in IHH/KS patients. Our results indicate ∼12% of KS males have KAL1 deletions, but intragenic deletions of the FGFR1, GNRH1, GNRHR, GPR54 and NELF genes are uncommon in IHH/KS.
doi:10.1093/molehr/gan027
PMCID: PMC2434956  PMID: 18463157
Kallmann syndrome; KAL1 gene; hypogonadotropic hypogonadism; idiopathic hypogonadotropic hypogonadism; MLPA
19.  Implementing genomic medicine in the clinic: the future is here 
Genetics in Medicine  2013;15(4):258-267.
Although the potential for genomics to contribute to clinical care has long been anticipated, the pace of defining the risks and benefits of incorporating genomic findings into medical practice has been relatively slow. Several institutions have recently begun genomic medicine programs, encountering many of the same obstacles and developing the same solutions, often independently. Recognizing that successful early experiences can inform subsequent efforts, the National Human Genome Research Institute brought together a number of these groups to describe their ongoing projects and challenges, identify common infrastructure and research needs, and outline an implementation framework for investigating and introducing similar programs elsewhere. Chief among the challenges were limited evidence and consensus on which genomic variants were medically relevant; lack of reimbursement for genomically driven interventions; and burden to patients and clinicians of assaying, reporting, intervening, and following up genomic findings. Key infrastructure needs included an openly accessible knowledge base capturing sequence variants and their phenotypic associations and a framework for defining and cataloging clinically actionable variants. Multiple institutions are actively engaged in using genomic information in clinical care. Much of this work is being done in isolation and would benefit from more structured collaboration and sharing of best practices.
Genet Med 2013:15(4):258–267
doi:10.1038/gim.2012.157
PMCID: PMC3835144  PMID: 23306799
medical genomics; practice standards

Results 1-19 (19)