A K Ryan

Bio: A K Ryan is an academic researcher from Newcastle University. The author has contributed to research in topics: Chromosome (genetic algorithm) & Microcephaly. The author has an hindex of 2, co-authored 4 publications receiving 1252 citations.

Spectrum of clinical features associated with interstitial chromosome 22q11 deletions: a European collaborative study.

Abstract: We present clinical data on 558 patients with deletions within the DiGeorge syndrome critical region of chromosome 22q11. Twenty-eight percent of the cases where parents had been tested had inherited deletions, with a marked excess of maternally inherited deletions (maternal 61, paternal 18). Eight percent of the patients had died, over half of these within a month of birth and the majority within 6 months. All but one of the deaths were the result of congenital heart disease. Clinically significant immunological problems were very uncommon. Nine percent of patients had cleft palate and 32% had velopharyngeal insufficiency, 60% of patients were hypocalcaemic, 75% of patients had cardiac problems, and 36% of patients who had abdominal ultrasound had a renal abnormality. Sixty-two percent of surviving patients were developmentally normal or had only mild learning problems. The majority of patients were constitutionally small, with 36% of patients below the 3rd centile for either height or weight parameters.

Smith-Lemli-Opitz syndrome: a variable clinical and biochemical phenotype.

Abstract: We have reviewed all known UK cases of Smith-Lemli-Opitz syndrome. Among 49 cases with proven 7-dehydrocholesterol reductase deficiency, half had been terminated or had died in infancy. The minimum incidence is 1 in 60,000. The frequent occurrence of hypospadias may account for 71% of recognised cases being male. Important common features which emerged include short thumbs, severe photosensitivity, aggressive behaviour, and atrioventricular septal defect. The typical facial appearance becomes less obvious with age and 20% of cases did not have 2/3 toe syndactyly. Biochemical measurements of serum 7-dehydrocholesterol did not correlate with clinical severity.

Two brothers with varying combinations of severe developmental delay, epilepsy, microcephaly, tetralogy of Fallot and hydronephrosis.

Abstract: We report on a sib pair who manifest a pattern of anomalies which appears to be unique and for which we are unable to provide a cytogenetic or molecular genetic explanation. While a number of their physical features are distinct, their overall appearance and pattern of neurological impairment suggest they suffer from the same genetic disorder.

Reply to letters regarding clinical features of chromosome 22q11 deletion

Abstract: One of the difficulties we face when we see anomalies/medical problems in people with a 22q1 1 deletion is deciding whether or not these are directly attributable to the microdeletion or are found by chance association. With what frequency does a second disorder need to occur before it can be said to be associated with the first? Dean et al commented on the occurrence of craniosynostosis in 22ql deletion patients. They reported an infant with a 22ql 1 deletion who had bilateral coronal and sagittal craniosynostosis. Subsequently this child was found to have a de novo P250R FGFR3 mutation. It is more likely that the craniosynostosis in this infant was the result of the FGFR3 mutation rather than the 22ql 1 deletion. However, the 5/548 (0.91%) reported in our series exceeds the highest population estimate they give. They state that the birth incidence of craniosynostosis varies between 1/3225 (0.03%) and 1/735 (0.13%) live births, with the upper 95% confidence interval being 1/518 (0.19%). However, we will proceed to obtain further clinical information on the five patients with craniosynostosis and undertake FGFR3 mutation analysis as they suggest. This should help to clarify whether craniosynostosis is a feature associated with 22ql 1 deletion. In contrast, Di Rocco et al comment on the absence of polyarthropathy/juvenile rheumatoid arthritis (JRA) in association with the 22ql 1 deletion in our series. Their own experience of 3/80 (3.75%) children at the Children's Hospital of Philadelphia having JRA gives an incidence of 50 times that of the general population. There were no reports of JRA/polyarthropathy in our series and it is unlikely that significant arthropathy would have been omitted from questionnaires. If the incidence is 3.75% we would have expected approximately 20 subjects in our series to have JRA. One of the strengths of our paper is the large number of patients reviewed. We hoped this study would clarify the incidence of uncommon features which may be overrepresented in published reports. Di Rocco et al also comment that other autoimmune conditions have been observed in chromosome 22ql 1 deletion syndrome. In

22q11.2 deletion syndrome

Abstract: 22q11.2 deletion syndrome (22q11.2DS) is the most common chromosomal microdeletion disorder, estimated to result mainly from de novo non-homologous meiotic recombination events occurring in approximately 1 in every 1,000 fetuses. The first description in the English language of the constellation of findings now known to be due to this chromosomal difference was made in the 1960s in children with DiGeorge syndrome, who presented with the clinical triad of immunodeficiency, hypoparathyroidism and congenital heart disease. The syndrome is now known to have a heterogeneous presentation that includes multiple additional congenital anomalies and later-onset conditions, such as palatal, gastrointestinal and renal abnormalities, autoimmune disease, variable cognitive delays, behavioural phenotypes and psychiatric illness - all far extending the original description of DiGeorge syndrome. Management requires a multidisciplinary approach involving paediatrics, general medicine, surgery, psychiatry, psychology, interventional therapies (physical, occupational, speech, language and behavioural) and genetic counselling. Although common, lack of recognition of the condition and/or lack of familiarity with genetic testing methods, together with the wide variability of clinical presentation, delays diagnosis. Early diagnosis, preferably prenatally or neonatally, could improve outcomes, thus stressing the importance of universal screening. Equally important, 22q11.2DS has become a model for understanding rare and frequent congenital anomalies, medical conditions, psychiatric and developmental disorders, and may provide a platform to better understand these disorders while affording opportunities for translational strategies across the lifespan for both patients with 22q11.2DS and those with these associated features in the general population.

High Rates of Schizophrenia in Adults With Velo-Cardio-Facial Syndrome

Abstract: Background Velo-cardio-facial syndrome (VCFS), a syndrome characterized by an increased frequency of schizophrenia and bipolar disorder, is associated with small interstitial deletions of chromosome 22q11. Methods We evaluated 50 adults with VCFS using a structured clinical interview (Schedules for Clinical Assessment in Neuropsychiatry or Psychiatric Assessment Schedule for Adults With Developmental Disability if IQ DSM-IV diagnosis. The schizophrenia phenotype in individuals with VCFS and schizophrenia was compared with a matched series of individuals with schizophrenia and without VCFS (n=12). The King's Schizotypy Questionnaire was administered to individuals with VCFS (n=41), their first-degree relatives (n=68), and a series of unrelated normal controls (n=316). All individuals with VCFS deleted for the N25 probe (n=48) were genotyped for a genetic polymorphism in the COMT gene that results in variations in enzymatic activity. Results Fifteen individuals with VCFS (30%) had a psychotic disorder, with 24% (n=12) fulfilling DSM-IV criteria for schizophrenia. In addition, 6 (12%) had major depression without psychotic features. The individuals with schizophrenia had fewer negative symptoms and a relatively later age of onset compared with those with schizophrenia and without VCFS. We found no evidence that possession of the low-activity COMT allele was associated with schizophrenia in our sample of individuals with VCFS. Conclusions The high prevalence of schizophrenia in this group suggests that chromosome 22q11 might harbor a gene or genes relevant to the etiology of schizophrenia in the wider population.

Genetic Basis for Congenital Heart Defects: Current Knowledge A Scientific Statement From the American Heart Association Congenital Cardiac Defects Committee, Council on Cardiovascular Disease in the Young

Abstract: The intent of this review is to provide the clinician with a summary of what is currently known about the contribution of genetics to the origin of congenital heart disease. Techniques are discussed to evaluate children with heart disease for genetic alterations. Many of these techniques are now available on a clinical basis. Information on the genetic and clinical evaluation of children with cardiac disease is presented, and several tables have been constructed to aid the clinician in the assessment of children with different types of heart disease. Genetic algorithms for cardiac defects have been constructed and are available in an appendix. It is anticipated that this summary will update a wide range of medical personnel, including pediatric cardiologists and pediatricians, adult cardiologists, internists, obstetricians, nurses, and thoracic surgeons, about the genetic aspects of congenital heart disease and will encourage an interdisciplinary approach to the child and adult with congenital heart disease.