Unrelated Parents Research Articles

P.1.7 Contiguous gene syndrome causing ColVI myopathy, dysmorphism, frontal atrophy and diaphragmatic hernia

Collagen VI (Col6) deficiency results in a broad spectrum of clinical manifestations ranging from Ullrich Congenital Muscular Dystrophy (UCMD) to Bethlem Myopathy with intermediate phenotypes. The COL6A3 gene encodes the α3(VI) subunit and maps to chromosome 2 in one of the most commonly deleted subtelomeric region, del2q37. UCMD is not classically associated with central nervous system involvement. However, some cases with intellectual disability have been reported, without any molecular explanation. We report the case of a 4-year-old boy born to unrelated French parents presenting with hypotonia, torticollis and club foot at birth. He had a motor delay (walked unaided at 3 years). Diaphragmatic hernia was discovered fortuitously and surgically corrected at 2y10m. At 3 years, he presented facial (mostly oral) and proximal weakness, distal hyperlaxity, no retractions and pectus excavatum. Moreover, we noted a mild facial dysmorphism with prominent forehead, down-slanted eyes, thin upper lip and low-set big ears. Scars from the diaphragmatic and muscle biopsy surgeries were slightly hypertrophic. The evolution was marked by seizures and two episodes of spontaneous fractures. Plasma CK levels were normal and the muscle biopsy findings were not specific. Cerebral MRI showed atrophy of the frontal lobe. Given the muscular phenotype, collagen VI immunolabeling was studied in cultured fibroblasts and demonstrated reduced Col secretion associated with intracytoplasmic retention. Currently aged 4y3m, the patient presents a positive evolution regarding motor and intellectual development. Interestingly, CGH array revealed a de novo translocation (2;4) with 2qter deletion (2q37.2–q37.3) and genomic gain at 4qter (4q35.1–q35.2), resulting in deletion of one COL6A3 allele. This is to our knowledge the 1st case report of a patient with Col6 myopathy phenotype associated with central nervous system involvement ascribed to a contiguous gene syndrome involving the COL6A3 locus.

Further characterization of atypical features in auriculocondylar syndrome caused by recessive PLCB4 mutations

Auriculocondylar syndrome (ACS) is a branchial arch syndrome typically inherited in an autosomal dominant fashion. Patients with ACS display the following core symptoms with varying severity: a specific malformation of the external ear, known as a "question mark ear," micrognathia and mandibular condyle hypoplasia. Recently, phospholipase C, β 4 (PLCB4) mutations were identified as the major cause of autosomal dominant ACS, with mutations of the PLCB4 catalytic domain predicted to have a dominant negative effect. In addition, one ACS patient born to related parents harbored a homozygous partial deletion of PLCB4, and presented with ACS plus central apnea and macropenis; these features had not been previously reported in association with ACS. His parents, each with a heterozygous partial PLCB4 deletion, were phenotypically normal, suggesting autosomal recessive inheritance of ACS, with complete loss of function of PLCB4 predicted in the patient. We herein describe two brothers with ACS caused by compound heterozygous splice site mutations in PLCB4. The patients were born to the same unrelated and healthy parents, with each parent harboring one of the mutations, indicating autosomal recessive ACS. Both patients reported here had mixed apneas, gastrointestinal transit defects and macropenis, in addition to typical craniofacial features of ACS. This is the first example of ACS caused by compound heterozygous splice site mutations in PLCB4, the second autosomal recessive case of ACS confirmed by molecular analysis, and strengthens the link between complete loss of function of PLCB4 and extra-craniofacial features.

A young child with pseudohypoaldosteronism type II by a mutation of Cullin 3

BackgroundPseudohypoaldosteronism type II (PHA II), also referred to as Gordon syndrome, is a rare renal tubular disease that is inherited in an autosomal manner. Though mutations in WNK1 and WNK4 partially account for this disorder, in 2012, 2 research groups showed that KLHL3 and CUL3 were the causative genes for PHA II. Here, we firstly report on the Japanese child of PHA II caused by a mutation of CUL 3.Case presentationThe patient was a 3-year-old Japanese girl having healthy unrelated parents. She was initially observed to have hyperkalemia, hyperchloremia, metabolic acidosis, and hypertension. A close investigation led to the diagnosis of PHA II, upon which abnormal findings of laboratory examinations and hypertension were immediately normalized by administering thiazides. Genetic analysis of WNK1 and WNK4 revealed no mutations. However, analysis of the CUL3 gene of the patient showed abnormal splicing caused by the modification of exon 9. The patient is currently 17 years old and does not exhibit hypertension or any abnormal findings on laboratory examination.ConclusionsIn this patient, CUL3 was found to play a fundamental role in the regulation of blood pressure, potassium levels, and acid–base balance.

Recurrent Pregnancy Loss in a Woman With NLRP7 Mutation

Recurrent hydatidiform moles is an uncommon occurrence. Over the past decade, genetic studies of women with multiple recurrent molar pregnancies have revealed that maternal mutations in two different genes, NLRP7 and C6orf221, result in recurrent moles. We report a 23 year old woman, born of unrelated parents, who has experienced three molar pregnancies in succession. Whilst the first pregnancy was classified as a complete hydatidiform mole, the second and third moles defied classification as complete or partial mole using conventional histology, p57 nuclear staining pattern and ploidy studies. Molecular and cytogenetic studies proved that all three molar pregnancies were diploid and biparental in origin. Gene sequencing analysis showed that the patient is homozygous for a previously described mutation in NLRP7. A SNP microarray ruled out the presence of deletion of the NLRP7 locus. This case draws attention to the fact that recurrent molar pregnancies may be the result of specific, identifiable gene mutations, even in patients from non-consanguineous backgrounds. When pathologists encounter patients with molar pregnancies that are diploid and p57 negative and yet have fetal elements such as nucleated red blood cells or immature fetal tissues, it should heighten their suspicion of a possible genetic basis and appropriate molecular genetic workup performed with counseling offered.

Somatic mosaicism in trichorhinophalangeal syndrome: a lesson for genetic counseling

Trichorhinophalangeal syndrome type I (TRPSI) is a genetic disorder characterized by sparse hair, a bulbous nasal tip, short stature with severe generalized shortening of all phalanges, metacarpal and metatarsal bones and cone-shaped epiphyses. This syndrome is caused by autosomal dominant mutations in the TRPS1 gene. However, because recurrence has been observed in siblings from healthy parents, an autosomal recessive mode of inheritance has also been suggested. We report on a male patient, born to healthy unrelated parents, with TRPSI. Using Sanger sequencing, we identified a mutation in the TRPS1 gene (c.2735 G>A, P.Cys912Tyr). The same mutation was detected as a 10% mosaic mutation by Pyrosequencing in blood-derived DNA from his healthy mother. To our knowledge, this is the first time that somatic mosaicism has been identified in TRPSI. This data combined with the observations of recurrences in siblings from healthy parents modifies the genetic counseling for TRPSI, which should discuss a 5-10 percent recurrence risk for healthy parents with an affected child because of the possibility of germinal mosaicism.

Confirmation of congenital mirror movements in a 19-month-old boy by detection of a de novo DCC mutation

Mirror movements (MM) are intentional movements of one limb (usually the upper one) that is involuntarily accompanied (mirrored) by the same movements of the opposite limb. Congenital MM (CMM) reflects dysfunctions and structural abnormalities of the motor network, including altered decussation of the corticospinal tract. CMM can be part of a more complex disorder such as Klippel-Feil syndrome, Kallmann syndrome, or congenital hemiplegia. Isolated CMM are autosomal dominantly inherited with incomplete penetrance. Heterozygous mutations in DCC, encoding the receptor for nectrin 1 that mediates axon guidance of developing neurons across the body's midline, have been described in patients with CMM. Recently, heterozygous RAD51 mutations have been detected in two DCC-mutation negative families. Mild MM can occur during development up to the age of 10 years causing difficulties in establishing an early clinical diagnosis. We report the case of a 19-month-old boy with CMM confirmed by genetic testing. He is the first child of healthy unrelated parents. Pregnancy, birth, postnatal adaptation, and groß motor milestones were normal; he walked without help at 15 months. At 3 months, he stretched his hands toward objects while balling his fists. He grabbed objects from age 7 months, but only with one hand at a time. When he turned objects for exploration, the other hand would turn as well. On examination at 19 months, he displayed typical MM of the hands. His cognition and speech were normal, there was no spasticity or hemiparesis, and odor discrimination seemed normal. Sequencing of the DCC gene identified heterozygous de novo 1-bp duplication (c.1999dupC/p.Arg667Profs*4).

The nature of nurture: Disentangling passive genotype–environment correlation from family relationship influences on children's externalizing problems.

The relationship between interparental conflict, hostile parenting, and children's externalizing problems is well established. Few studies, however, have examined the pattern of association underlying this constellation of family and child level variables while controlling for the possible confounding presence of passive genotype–environment correlation. Using the attributes of 2 genetically sensitive research designs, the present study examined associations among interparental conflict, parent-to-child hostility, and children's externalizing problems among genetically related and genetically unrelated mother–child and father–child groupings. Analyses were conducted separately by parent gender, thereby allowing examination of the relative role of the mother–child and father–child relationships on children's behavioral outcomes. Path analyses revealed that for both genetically related and genetically unrelated parents and children, indirect associations were apparent from interparental conflict to child externalizing problems through mother-to-child and father-to-child hostility. Associations between interparental conflict and parent-to-child hostility across genetically related and genetically unrelated parent–child groupings were significantly stronger for fathers compared to mothers. Results are discussed with respect to the role of passive genotype–environment correlation as a possible confounding influence in interpreting research findings from previous studies conducted in this area. Implications for intervention programs focusing on family process influences on child externalizing problems are also considered.

Two novel mutations of the CYP11B2 gene in a Japanese patient with aldosterone deficiency type 1

Isolated hypoaldosteronism is a rare and occasionally life-threatening cause of salt wasting in infancy. A 2-month-old Japanese boy of unrelated parents was examined for failure to thrive and poor weight gain. Laboratory findings were hyponatremia, hyperkalemia, high plasma renin and low aldosterone levels. Spot urine analysis by gas chromatography-mass spectrometry (GC-MS) showed that urinary excretion of corticosterone metabolites was elevated. Whereas excretion of 18-hydroxycortricosterone metabolites was within the normal range, excretion of aldosterone metabolites was undetectable. The patient was therefore suspected to have aldosterone synthase deficiency type 1. Sequence analysis of CYP11B2, the gene encoding aldosterone synthase (CYP11B2), showed that the patient was a compound heterozygote for c.168G>A, p.W56X in exon 1 and c.1149C>T, p.R384X in exon 7. p.W56X was inherited from his mother and p.R384X was from his father. Since both alleles contain nonsense mutations, a lack of CYP11B2 activity was speculated to cause his condition. To our knowledge, this is the first Japanese patient in which the molecular basis of aldosterone synthase deficiency type 1 has been clarified. This case also indicates that spot urinary steroid analysis is useful for diagnosis.

Logging On: Evaluating an Online Support Group for Parents of Children with Autism Spectrum Disorders

Twenty mothers participated in an online support group for parents of children with autism spectrum disorders. Twenty-five unrelated parents participated in a no-treatment control group. The participants completed online questionnaires prior to and following the 4-month support group, to evaluate changes in mood, anxiety, parenting stress, and positive perceptions. No significant differences between the groups or across time were found. However, parents who participated in the group reported being satisfied with the support they received and finding the group helpful. Issues related to participant recruitment and retention are discussed. Further research is required to investigate the efficacy of online support groups for parents of children with ASD.

Genetic improvement for yield and tuber size in Andigena potatoes (Solanum tuberosum subsp andigena) after one cycle of recurrent selection

Improvement of Andigena genotypes for tuber characters was attempted by making Andigena × Andigena crosses. Andigena accessions could be considerably improved for characters like yield and tuber size by crossing among themselves. Progenies of different cross types like full-sibs, half-sibs, back crosses and cross between unrelated parents among the improved Andigena clones of first cycle of selection were evaluated for tuber characters related to yield to know the best approach for further improvement of Andigena clones for these characters. Half-sibs and crosses between unrelated parents progenies were significantly better than full-sibs and back crosses progenies for the characters yield and average tuber weight, suggesting thereby that for further improvement of Andigena it is important to maintain heterozygosity. The results of the present study show that recurrent selection technique can be useful for improvement of Andigena genotypes.

Poor growth in an infant with cystic fibrosis due to an antenatal perforation and incomplete bowel obstruction

The infant was born at term weighing 2860 g, the first child of healthy unrelated parents. Routine antenatal scans had been normal. Delivery was via a breech presentation and clinical signs of congenital dysplastic hips (CDH) were detected on newborn examination and a referral wasmade to an orthopaedic surgeon. He passed meconium within the first 24 h and was discharged on the second day of life. At 16 days of age he was readmitted with a short history of loose stools and poor feeding. He had lost 22% of his birth weight. He was hyponatraemic with a conjugated hyperbilirubinaemia and an elevated c-reactive protein. He was treated for presumed sepsis. A week later cystic fibrosis (CF) was suggested on newborn screening results (homozygous p.Phe508del). Treatment was

Clinical Reasoning: A young man with progressive subcortical lesions and optic nerve atrophy

The male patient is the third child of unrelated Japanese parents. His older sister had tachypnea and feeding difficulties, and died at 5 days of age. The patient was delivered at term (birthweight, 3.8 kg), following an unremarkable pregnancy. He presented with tachypnea, metabolic acidosis, and hyperammonemia (944 μmol · L−1) at 6 days. ### Questions for consideration: 1. What is the differential for infantile presentation of hyperammonemia in the neonatal period? 2. What laboratory tests would you pursue? GO TO SECTION 2 Hyperammonemia occurs in urea cycle disorders (e.g., ornithine transcarbamylase deficiency) and organic acidurias (e.g., methylmalonic aciduria, propionic aciduria, and isovaleric aciduria) and fatty acid oxidation defects (e.g., multiple acyl-CoA dehydrogenase deficiency). The existence of acidosis with ketosis indicates organic aciduria, whereas respiratory alkalosis is observed in urea cycle defects. Diagnosis is based on quantitative assay of amino acids and acylcarnitines from dried blood and organic acids in urine samples. ### Case: part 2. Elevated levels of 2-methylcitric acid and 3-hydroxypropionic acid were found in the urine. The plasma propionic acid concentration was increased (4.5 mg · dL−1), and propionyl-CoA …

Congenital Familial Subglottic Stenosis

Objective: Congenital stenosis may be caused by either a small cricoid cartilage or a thick submucosa secondary to a failure of canalization of the subglottic lumen. Acquired subglottic stenosis is caused by trauma. Congenital subglottic stenosis is a well-known cause of stridor in infancy. It usually occurs sporadically and familial occurrence is rare. Method: Case series. Pediatric tertiary referral center.Three children who presented with subglottic stenosis born to consanguineous parents were identified. For the literature research, reports published from 1950 to January 2012 were retrieved. We also screened bibliographies of the collected articles to identify pertinent reports. Results: Three Asian children were born with congenital subglottic stenosis for closely related consanguineous parents. Their presentation, family tree, genetic tests, associated features, and treatment will be discussed. All patients underwent laryngotracheal reconstruction. Conclusion: Congenital familial subglottic stenosis in unrelated parents has been reported previously but not in consanguineous parents. Family genetic work up is recommended. Further genetic research is needed to assess the mode of possible heritage in these cases.

Two independent de novo mutations as a cause for neurofibromatosis type 1 and Noonan syndrome in a single family

Here we report on a family with two siblings born to unrelated healthy parents, one with neurofibromatosis type 1 (NF1) and the other with Noonan syndrome (NS). Molecular investigations performed on the NF1 and PTPN11 genes showed two independent de novo mutations as a cause for NF1 in the NF1 proband and NS in her affected brother. Both de novo mutations were potentially of paternal origin, given the advanced paternal age at the time of conception.

MFN2, a new gene responsible for mitochondrial DNA depletion

Sir, we read with great interest the paper by Rouzier et al. (2012) reporting a novel dominant MFN2 missense mutation (c.629A>T, p.D210V) in a large family displaying an optic atrophy ‘plus’ phenotype. Importantly, the authors identified MFN2 as a new gene implicated in mitochondrial DNA instability as they found multiple mitochondrial DNA deletions in skeletal muscle of two adult patients. Moreover, they have shown that mitochondrial fusion is necessary to repair stress-induced damage to mitochondrial DNA. Here, we report a child with an early-onset progressive multi-systemic disorder and carrying a novel MFN2 missense mutation responsible for mitochondrial DNA depletion in skeletal muscle. This girl was the second child of healthy unrelated parents, born after an uneventful pregnancy. Her birth weight was 2700 g [−2 standard deviations (SD)], her length 45.5 cm (−2 SD) and her head circumference 35 cm (mean). At the age of 6 months she was examined because of developmental delay with hypotonia, decreased rate of growth in head circumference (−2 SD), failure to thrive and severe gastro-oesophageal reflux. Brain MRI, EEG, brainstem auditory evoked potentials, metabolic and genetic investigations were all normal. At 3 years of age, the patient could only stand up when aided and had no language acquisition although her level of understanding seemed good as did her social interaction and behaviour. Drooling, abnormal ocular pursuit, ataxia, dysmetria, areflexia, weakness of limbs and near permanent abnormal movements appeared progressively thereafter. EMG disclosed an axonal sensorimotor neuropathy. At 5 years of age, brainstem auditory evoked potentials revealed hearing loss on the right side and the amplitude of visual evoked responses was decreased while the electroretinogram was normal. Complementary aetiological explorations were negative. Orthopaedic …

A rare presentation of myasthenia gravis

Background and aims Myasthenia gravis (MG) is a heterogeneous disorder in which antibodies are directed at the postsynaptic membrane of the neuromuscular junction, leading to varying degrees of muscle weakness and fatigability. Ptosis, dysphagia, dysphonia and proximal weakness are common presenting symptoms in children. We report a case of 14 months old male child presenting with inspiratory stridor resembling group. Methods and results A 14 months old child presented to accident and emergency (A&E) of a district general hospital for the third time in a week, with barking cough, noisy breathing and stridor. His symptoms had worsened over the last 24 hours resulting in a choking episode and difficulty in feeding. This was preceded by a week9s history of cough, cold, diarrhoea and vomiting. He was treated as croup on first two attendances in A&E. He was born at term by normal vaginal delivery to unrelated Caucasian parents. He was diagnosed with laryngomalacia at two months of age, when he presented to paediatric outpatients for noisy breathing. This improved by 6 months of age. There was no family history of neuromuscular disorders. Examination revealed tachycardia, signs of respiratory distress, stridor, drooling from mouth and drooping eyelids. He was transferred to tertiary centre for intensive monitoring and further investigations. His initial treatment based on a presumptive diagnosis of croup did not show any response. Further investigations included MRI brain which was normal. After a failed extubation, he was subjected to tensilon test to which a partial response was noted. He was commenced on pyridostigmine and prednisolone. Repetitive nerve stimulation and stimulated single fibre electromyography confirmed the diagnosis of MG. Acetyl choline receptor antibodies were undetectable. Results of genetic screening are still awaited. Prednisolone was weaned in next 4- 6 months. He remains well on pyridostigmine. Conclusion Myasthenia gravis can present with involvement of any muscle innervated by cranial nerves and the diagnosis should be entertained when muscular weakness or fatigability is demonstrated. Although an uncommon cause Myasthenia gravis should be included in differential diagnosis of stridor.

Further characterization of acro-renal-uterine-mandibular syndrome

List of key featuresEctrodactylyMicrognathiaMandibular hypoplasiaCleft palateRenal anomaliesCase reportThe proposita is the only child of unrelated parents. Her mother had untreated vitiligo. She had no antenatal problems and was not exposed to any known teratogens. The child was delivered at full t

HLA‐DRB1, ‐DQA1 and ‐DQB1 Alleles and Haplotypes in First‐Generation Pakistani Immigrants in Norway

Human leucocyte antigen (HLA) polymorphisms among immigrants from Pakistan have not been well investigated. Immigration to Norway started in the late 1960s for working purposes. From 1975, immigration was mainly for marriages and family reunion. When recruiting couples for a birth cohort study, we ended up with 65.5% of the 374 parents genotyped being closely related. This was also reflected in that 21% of newborns were homozygotes for their DRB1-DQA1-DQB1 genotype. For being able to study HLA class II genes frequencies among unrelated individuals, we had to exclude 195 of the parents from data analysis. High-resolution typing for the DRB1 locus, low/intermediate for the DQA1 locus and resolution genotyping for the DQB1 locus were performed in all the 179 parents and their newborns from the Punjab province of Pakistan. We identified 25 DRB1, nine DQA1 and 14 DRB1 alleles in the 179 unrelated parents included in our analysis. The most frequent alleles were DRB1*03:01:01 (15.9%) and DRB1*07:01:01 (15.9%), DQA1*01:03 (22.1%) and DQB1*02:01:01 (26.0%). Forty-one haplotypes were identified, including DRB1*13:02:01-DQA1*01:02-DQB1*06:03:01, not earlier reported. Supported by the few earlier reports on Pakistani groups living in Pakistan, it appears that alleles found among those living in Norway are of Indo-European or mixed ethnic origin. This study provides the first comprehensive report of HLA class II alleles and haplotypes in Norwegian Pakistani immigrants. When the unrelated parents were compared with all parents genotyped, there were, however, no significant differences in allele frequencies, confirming that consanguineous marriages are usual in Pakistan.

A 15-month-old boy with reduced consciousness and convulsion

A previously healthy 15-month-old boy was admitted to our ospital with fever, reduced consciousness, and convulsion. He was he first child of unrelated healthy parents. None of his family had ad a febrile illness for at least 1 month before his admission. He lso had a generalized convulsion lasting for 3 min on the day of dmission. He was transferred to our hospital because a local peditrician noticed mildly decreased responsiveness. On admission, the patient had a temperature of 40.6 ◦C, heart ate of 148 bpm, respiration rate of 52/min, and oxygen saturaion of 98% in room air. Physical examination was unremarkable xcept for nuchal rigidity. Neurological examination revealed mild eduction of consciousness with a Glasgow Coma Scale score of 3. Deep tendon reflexes were normal. Laboratory examination

Consanguinity in Centre d’Étude du Polymorphisme Humain (CEPH) pedigrees

A set of Centre d'Étude du Polymorphisme Humain (CEPH) cell lines serves as a large reference collection that has been widely used as a benchmark for allele frequencies in the analysis of genetic variants, to create linkage maps of the human genome, to study the genetics of gene expression, to provide samples to the HapMap and 1000 Genomes projects, and for a variety of other applications. An explicit feature of the CEPH collection is that these multigenerational families represent reference panels of known relatedness, consisting mostly of three-generation pedigrees with large sibships, two parents, and grandparents. We applied identity-by-state (IBS) and identity-by-descent (IBD) methods to high-density genotype data from 186 CEPH individuals in 13 families. We identified unexpected relatedness between nominally unrelated grandparents both within and between pedigrees. For one pair, the estimated Cotterman coefficient of relatedness k1 exceeded 0.2, consistent with one-eighth sharing (eg, first-cousins). Unexpectedly, significant IBD2 values were discovered in both second-degree and parent-child relationships. These were accompanied by regions of homozygosity in the offspring, which corresponded to blocks lacking IBS0 in purportedly unrelated parents, consistent with inbreeding. Our findings support and extend a 1999 report, based on the use of short tandem-repeat polymorphisms, that several CEPH families had regions of homozygosity consistent with autozygosity. We benchmarked our IBD approach (called kcoeff) against both RELPAIR and PREST software packages. Our findings may affect the interpretation of previous studies and the design of future studies that rely on the CEPH resource.