Search

ObjectiveTo determine the yield of genetic diagnoses using chromosomal microarray (CMA) and trio whole exome sequencing (WES), separately and combined, among patients with cryptogenic cerebral palsy (CP).MethodsTrio WES of patients with prior CMA analysis for cryptogenic CP, defined as disabling, non-progressive motor symptoms beginning before the age of 3 years without known cause.ResultsGiven both CMA analysis and trio WES, clinically significant genetic findings were identified for 58% of patients (26 of 45). Diagnoses were eight large CNVs detected by CMA and 18 point mutations detected by trio WES. None had more than one severe mutation. Approximately half of events (14 of 26) were de novo. Yield was significantly higher in patients with CP with comorbidities (69%, 22 of 32) than in those with pure motor CP (31%, 4 of 13; p=0.02). Among patients with genetic diagnoses, CNVs were more frequent than point mutations among patients with congenital anomalies (OR 7.8, 95% CI 1.2 to 52.4) or major dysmorphic features (OR 10.5, 95% CI 1.4 to 73.7). Clinically significant mutations were identified in 18 different genes: 14 with known involvement in CP-related disorders and 4 responsible for other neurodevelopmental conditions. Three possible new candidate genes for CP were ARGEF10, RTF1 and TAOK3.ConclusionsCryptogenic CP is genetically highly heterogeneous. Genomic analysis has a high yield and is warranted in all these patients. Trio WES has higher yield than CMA, except in patients with congenital anomalies or major dysmorphic features, but these methods are complementary. Patients with negative results with one approach should also be tested by the other.

Background Progressive cerebello-cerebral atrophy (PCCA) leading to profound mental retardation, progressive microcephaly, spasticity and early onset epilepsy, was diagnosed in four non-consanguineous apparently unrelated families of Jewish Moroccan ancestry. Common founder mutation(s) were assumed. Methods Genome-wide linkage analysis and whole exome sequencing were done, followed by realtime PCR and immunofluorescent microscopy. Results Genome-wide linkage analysis mapped the disease-associated gene to 0.5 Mb on chromosome 17p13.3. Whole exome sequencing identified only two mutations within this locus, which were common to the affected individuals: compound heterozygous mutations in VPS53 , segregating as expected for autosomal recessive heredity within all four families, and common in Moroccan Jews (∼1:37 carrier rate). The Golgi-associated retrograde protein (GARP) complex is involved in the retrograde pathway recycling endocytic vesicles to Golgi; c.2084A>G and c.1556+5G>A VPS53 founder mutations are predicted to affect the C-terminal domain of VPS53, known to be critical to its role as part of this complex. Immunofluorescent microscopy demonstrated swollen and abnormally numerous CD63 positive vesicular bodies, likely intermediate recycling/late endosomes, in fibroblasts of affected individuals. Conclusions Autosomal recessive PCCA type 2 is caused by VPS53 mutations.

Editor—Freeman-Sheldon syndrome (FSS) (McKusick 193700), described in 1938, is characterised by a whistling face with a long philtrum, a puckered mouth, microstomia, H shaped cutaneous dimpling on the chin, multiple joint contractures with camptodactyly, ulnar deviation of the fingers, bilateral talipes equinovarus, and kyphoscoliosis.1 Burian rediscovered the entity and called it the “whistling face syndrome”.2 There is genetic heterogeneity.3-6 Both autosomal dominant7 8 and recessive inheritance9-12have been described. The psychomotor development of affected children is usually normal in the autosomal dominant forms,6 13 14 although mild motor delay attributable to joint anomalies has been reported occasionally.3 15-18 A few patients with severe developmental retardation have been described, all with autosomal recessive inheritance.19-22 We describe a child who presented from birth with distal arthrogryposis, profound mental retardation, severe hypotonia, and whistling face. The severe neurological involvement precludes him from having FSS according to the classification of Bamshad et al .23 We suggest that patients with a whistling face, distal contractures, and severe neurological involvement should be diagnosed as having a separate autosomal recessive syndrome. The patient was the first child of non-consanguineous, healthy, Moroccan Jews. The pregnancy was attained by in vitro fertilisation and was unremarkable. He was born at 42 weeks' gestation. Apgar scores were 4 at one minute and 6 at five minutes; pH was 7.11 and improved with bicarbonate infusion. A single seizure on the second day did not recur following phenobarbital therapy. Hypotonia with scarce spontaneous movements but increased reflexes was first noticed then. Length, weight, and head circumferences were on the 50th centile. He was first evaluated at the age …

The combination of microcephaly, spasticity, and profound mental retardation is usually found in children with severe perinatal asphyxia or congenital infection. These children are commonly diagnosed as having cerebral palsy. However, in some children there is no evidence of a perinatal insult and there may be familial recurrence.1 The London Dysmorphology Database2 offers 104 genetic syndromes that include these features. However, most of them also show dysmorphism and other organ involvement. Twenty-three of these syndromes are the result of an identified inborn error of metabolism. In some genetic syndromes the microcephaly may be progressive and brain neuroimaging may show cortical or cerebellar atrophy.3 Cerebellar atrophy can be associated with spasticity and profound mental retardation in pontocerebellar hypoplasia type 2 (PCH 2). We describe seven patients from six non-consanguineous Sephardi Jewish families with a previously undescribed syndrome of profound mental retardation, progressive microcephaly, and severe spasticity. Radiologically, repeat magnetic resonance imaging showed progressive cerebellar atrophy followed by cerebral atrophy involving both white and grey matter. An extensive metabolic evaluation was normal. Table 1 shows seven patients (five female), identified in two paediatric neurology clinics in Israel, with a similar clinical picture of profound mental retardation, progressive microcephaly, and severe spasticity. All had the same radiological features consistent with progressive cerebellar atrophy and cerebral atrophy involving both white and grey matter. View this table: Table 1 Patient characteristics Five patients were isolated cases and two were sisters. All families were non-consanguineous Sephardi Jews of either Moroccan or Iraqi origin. All the parents and unaffected sibs were healthy and neurologically intact. Age range was 18 months to 19 years. All patients were the product of a normal pregnancy and delivery. Head circumference was normal at birth. Progressive microcephaly became evident during the first year of life, ranging from 2 to 5 SD below the norm. …

Editor—The CHARGE association is an increasingly recognised pattern of congenital anomalies comprising colobomata, heart defects, choanal atresia, retarded growth and development, hypoplastic genitalia, and ear abnormalities/deafness.1 We report a case of CHARGE association with a de novo chromosomal aberration, 46,X,+der(X)t(X;2), which was detected by spectral karyotyping. The proband, an 11 year old girl, was the term product of a normal pregnancy and delivery to healthy and unrelated parents. She has a healthy younger brother. The family history is unremarkable for mental retardation and congenital malformations. Birth weight was 2870 g and Apgar scores were 7 and 7 at one and five minutes, respectively. Bilateral choanal atresia was diagnosed at birth and she was admitted to hospital with an airway for two months. At the age of 8 months, she underwent a surgical repair but left choanal stenosis persisted. At the age of 5 years, after recurrences of purulent otitis media, she underwent an adenoidectomy. At the age of 8 years, a heart murmur was heard and an echocardiogram and cardiac catheterisation showed minimal valvar pulmonary stenosis and partial anomalous venous return. Renal ultrasound showed mild enlargement of the left kidney with calculi. Because of additional growth and developmental delay, a chromosome analysis was performed on blood lymphocytes at the age of 6 years and …