The prevalence and phenotypic range associated with biallelic PKDCC variants.

PKDCC encodes a component of Hedgehog signalling required for normal chondrogenesis and skeletal development. Although biallelic PKDCC variants have been implicated in rhizomelic shortening of limbs with variable dysmorphic features, this association was based on just two patients. In this study, data from the 100 000 Genomes Project was used in conjunction with exome sequencing and panel-testing results accessed via international collaboration to assemble a cohort of eight individuals from seven independent families with biallelic PKDCC variants. The allelic series included six frameshifts, a previously described splice-donor site variant and a likely pathogenic missense variant observed in two families that was supported by in silico structural modelling. Database queries suggested that the prevalence of this condition is between 1 of 127 and 1 of 721 in clinical cohorts with skeletal dysplasia of unknown aetiology. Clinical assessments, combined with data from previously published cases, indicate a predominantly upper limb involvement. Micrognathia, hypertelorism and hearing loss appear to be commonly co-occurring features. In conclusion, this study strengthens the link between biallelic inactivation of PKDCC and rhizomelic limb-shortening and will enable clinical testing laboratories to better interpret variants in this gene.

The different clinical facets of SYN1-related neurodevelopmental disorders.

Synapsin-I (SYN1) is a presynaptic phosphoprotein crucial for synaptogenesis and synaptic plasticity. Pathogenic SYN1 variants are associated with variable X-linked neurodevelopmental disorders mainly affecting males. In this study, we expand on the clinical and molecular spectrum of the SYN1-related neurodevelopmental disorders by describing 31 novel individuals harboring 22 different SYN1 variants. We analyzed newly identified as well as previously reported individuals in order to define the frequency of key features associated with these disorders. Specifically, behavioral disturbances such as autism spectrum disorder or attention deficit hyperactivity disorder are observed in 91% of the individuals, epilepsy in 82%, intellectual disability in 77%, and developmental delay in 70%. Seizure types mainly include tonic-clonic or focal seizures with impaired awareness. The presence of reflex seizures is one of the most representative clinical manifestations related to SYN1. In more than half of the cases, seizures are triggered by contact with water, but other triggers are also frequently reported, including rubbing with a towel, fever, toothbrushing, fingernail clipping, falling asleep, and watching others showering or bathing. We additionally describe hyperpnea, emotion, lighting, using a stroboscope, digestive troubles, and defecation as possible triggers in individuals with SYN1 variants. The molecular spectrum of SYN1 variants is broad and encompasses truncating variants (frameshift, nonsense, splicing and start-loss variants) as well as non-truncating variants (missense substitutions and in-frame duplications). Genotype-phenotype correlation revealed that epileptic phenotypes are enriched in individuals with truncating variants. Furthermore, we could show for the first time that individuals with early seizures onset tend to present with severe-to-profound intellectual disability, hence highlighting the existence of an association between early seizure onset and more severe impairment of cognitive functions. Altogether, we present a detailed clinical description of the largest series of individuals with SYN1 variants reported so far and provide the first genotype-phenotype correlations for this gene. A timely molecular diagnosis and genetic counseling are cardinal for appropriate patient management and treatment.

POLD1 Germline Mutations in Patients Initially Diagnosed with Werner Syndrome.

Segmental progeroid syndromes are rare, heterogeneous disorders characterized by signs of premature aging affecting more than one tissue or organ. A prototypic example is the Werner syndrome (WS), caused by biallelic germline mutations in the Werner helicase gene (WRN). While heterozygous lamin A/C (LMNA) mutations are found in a few nonclassical cases of WS, another 10%-15% of patients initially diagnosed with WS do not have mutations in WRN or LMNA. Germline POLD1 mutations were recently reported in five patients with another segmental progeroid disorder: mandibular hypoplasia, deafness, progeroid features syndrome. Here, we describe eight additional patients with heterozygous POLD1 mutations, thereby substantially expanding the characterization of this new example of segmental progeroid disorders. First, we identified POLD1 mutations in patients initially diagnosed with WS. Second, we describe POLD1 mutation carriers without clinically relevant hearing impairment or mandibular underdevelopment, both previously thought to represent obligate diagnostic features. These patients also exhibit a lower incidence of metabolic abnormalities and joint contractures. Third, we document postnatal short stature and premature greying/loss of hair in POLD1 mutation carriers. We conclude that POLD1 germline mutations can result in a variably expressed and probably underdiagnosed segmental progeroid syndrome.

Outcomes in children with Noonan syndrome and hypertrophic cardiomyopathy: a study from the Pediatric Cardiomyopathy Registry.

BACKGROUND: Studies of cardiomyopathy in children with Noonan syndrome (NS) have been primarily small case series or cross-sectional studies with small or no comparison groups. METHODS: We used the Pediatric Cardiomyopathy Registry database to compare the survival experience of children with NS and hypertrophic cardiomyopathy (HCM) with children with idiopathic or familial HCM and to identify clinical and echocardiographic predictors of clinical outcomes. RESULTS: Longitudinal data in 74 children with NS and HCM and 792 children with idiopathic or familial isolated HCM were compared. Children with NS were diagnosed with HCM before 6 months old more often (51%) than children with HCM (28%) and were more likely to present with congestive heart failure (CHF) (24% vs 9%). The NS cohort had lower crude survival than the group with other HCM (P = .03), but survival did not differ after adjustment for CHF and age at diagnosis. Within the NS cohort (1-year survival 78%), a diagnosis of HCM before age 6 months with CHF resulted in 31% 1-year survival. Lower height-for-age z score (hazard ratio 0.26, P = .005) in place of CHF and lower left ventricular fractional shortening z score (hazard ratio 0.79, P = .04) also independently predicted mortality. CONCLUSIONS: Patients with NS with HCM have a worse risk profile at presentation compared with other children with HCM, resulting in significant early mortality (22% at 1 year). Decreased height-for-age and lower, although still supranormal, left ventricular fractional shortening z score are independent predictors of mortality in patients with NS with HCM. Such patients should have an aggressive therapeutic approach including potential listing for cardiac transplantation.

Deletion 17q12 is a recurrent copy number variant that confers high risk of autism and schizophrenia.

Autism spectrum disorders (ASD) and schizophrenia are neurodevelopmental disorders for which recent evidence indicates an important etiologic role for rare copy number variants (CNVs) and suggests common genetic mechanisms. We performed cytogenomic array analysis in a discovery sample of patients with neurodevelopmental disorders referred for clinical testing. We detected a recurrent 1.4 Mb deletion at 17q12, which harbors HNF1B, the gene responsible for renal cysts and diabetes syndrome (RCAD), in 18/15,749 patients, including several with ASD, but 0/4,519 controls. We identified additional shared phenotypic features among nine patients available for clinical assessment, including macrocephaly, characteristic facial features, renal anomalies, and neurocognitive impairments. In a large follow-up sample, the same deletion was identified in 2/1,182 ASD/neurocognitive impairment and in 4/6,340 schizophrenia patients, but in 0/47,929 controls (corrected p = 7.37 × 10⁻5). These data demonstrate that deletion 17q12 is a recurrent, pathogenic CNV that confers a very high risk for ASD and schizophrenia and show that one or more of the 15 genes in the deleted interval is dosage sensitive and essential for normal brain development and function. In addition, the phenotypic features of patients with this CNV are consistent with a contiguous gene syndrome that extends beyond RCAD, which is caused by HNF1B mutations only.

A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay.

We report the identification of a recurrent, 520-kb 16p12.1 microdeletion associated with childhood developmental delay. The microdeletion was detected in 20 of 11,873 cases compared with 2 of 8,540 controls (P = 0.0009, OR = 7.2) and replicated in a second series of 22 of 9,254 cases compared with 6 of 6,299 controls (P = 0.028, OR = 2.5). Most deletions were inherited, with carrier parents likely to manifest neuropsychiatric phenotypes compared to non-carrier parents (P = 0.037, OR = 6). Probands were more likely to carry an additional large copy-number variant when compared to matched controls (10 of 42 cases, P = 5.7 x 10(-5), OR = 6.6). The clinical features of individuals with two mutations were distinct from and/or more severe than those of individuals carrying only the co-occurring mutation. Our data support a two-hit model in which the 16p12.1 microdeletion both predisposes to neuropsychiatric phenotypes as a single event and exacerbates neurodevelopmental phenotypes in association with other large deletions or duplications. Analysis of other microdeletions with variable expressivity indicates that this two-hit model might be more generally applicable to neuropsychiatric disease.

Characteristics and outcomes of cardiomyopathy in children with Duchenne or Becker muscular dystrophy: a comparative study from the Pediatric Cardiomyopathy Registry.

OBJECTIVE: The aim of this study was to determine in pediatric Duchenne (DMD) and Becker muscular dystrophy (BMD) or other dilated cardiomyopathies (ODCM) whether outcomes differ by diagnosis. BACKGROUND: Children with dilated cardiomyopathy are treated as a single undifferentiated group. METHODS: This cohort study of 128 children with DMD, 15 with BMD, and 312 with ODCM uses outcome measures of left ventricular (LV) size and function, death, heart transplant, and death or transplant. RESULTS: At cardiomyopathy diagnosis, the DMD and BMD groups had similar mean ages (14.4 and 14.6 years), prevalence of congestive heart failure (CHF) (30% and 33%), and LV fractional shortening (FS) Z-scores (median, -5.2 for DMD and -6.7 for BMD). The BMD group had more severe mitral regurgitation (P = .05) and a higher mean LV end-diastolic dimension Z-score than the DMD group (2.9 +/- 1.5 vs 1.2 +/- 1.9, P = .002). Duchenne muscular dystrophy group survival was lower than in BMD or ODCM groups (P = .06) at 5 years (57%, 100%, and 71%, respectively). In BMD, 25% received cardiac transplants within 0.4 years of cardiomyopathy diagnosis. The combined DMD and BMD group had less LV dilation and a closer-to-normal LV FS at cardiomyopathy diagnosis than the ODCM group. After 2 years, LV dilation increased, and LV FS did not change in the combined DMD and BMD group; for ODCM patients, LV dilation did not progress, and LV FS improved. CONCLUSIONS: Children with DMD and cardiomyopathy have a higher mortality. Becker muscular dystrophy has a high heart transplantation rate in the 5 years after diagnosis of cardiomyopathy. Serial echocardiography demonstrates a different disease course for DMD and BMD patients compared with ODCM patients.

Dysmorphic and anthropometric outcomes in 6-year-old prenatally cocaine-exposed children.

Dysmorphologic and anthropometric assessments were performed on 154 6-year-old children prenatally exposed to cocaine (PCE) and 131 high-risk controls (NCE) of similar race and social class. Adjusted mean height z scores demonstrated a dose-response with metahydroxybenzoylecgonine above a threshold of 100 ng/g of meconium and greater cocaine exposure predicted lower weight for height z score. Higher average alcohol exposure throughout pregnancy and 3rd trimester predicted lower head circumference and weight z scores, respectively. Severity of marijuana use also predicted lower height for age but greater weight for height. There was not an increased rate of minor anomalies among the PCE cohort, nor was a consistent phenotype identified. After controlling for covariates, higher average prenatal cigarette exposure predicted higher incidence of cranial facial abnormalities. First trimester alcohol exposure predicted greater rates of ear abnormalities and third trimester marijuana exposure predicted greater rates of chest and head shape abnormalities. These finding indicate that prenatal cocaine exposure has a negative effect on specific growth outcomes including standardized height and weight for height, but not a systematic pattern of structural abnormalities.