Phenylketonuria (PKU) is a genetic disorder with amino acid metabolic defect, which does great harms to the development of newborns and children. Early diagnosis and treatment can effectively prevent the disease progression. Here we developed a PKU screening model using random forest classifier (RFC) to improve PKU screening performance with excellent sensitivity, false positive rate (FPR) and positive predictive value (PPV) in all the validation dataset and two testing Chinese populations. RFC represented outstanding advantages comparing several different classification models based on machine learning and the traditional logistic regression model. RFC is promising to be applied to neonatal PKU screening.

Folic acid (FA) supplementation before and during the first trimester can reduce the risk of occurrence of preterm delivery (PTD). Preconception body mass index (BMI) is also associated with PTD. This study aimed to investigate the combined effect of FA supplements and preconception BMI on the risk of PTD. The data of a cohort from 2010–2011 that was obtained through a preconception care service in China was used (including 172,206 women). A multivariable regression model was used to investigate the association between maternal preconception conditions and the risk of PTD. The interaction of preconception BMI and FA supplementation was measured by a logistic regression model. Taking FA supplements in the preconception period or in the first trimester reduced the risk of PTD (odds ratio [OR] = 0.58 and OR = 0.61, respectively). Women with an abnormal BMI had an increased risk of PTD (OR = 1.09, OR = 1.10, and OR = 1.17 for underweight, overweight, and obese, respectively). Preconception BMI showed an interaction with the protective effect of FA supplementation for PTD. With regard to the interaction of FA supplementation, the adjusted odds ratio (aOR) was 0.57 (95 % CI: 0.51, 0.64) in underweight women, 0.85 (95 % CI: 0.73, 0.98) in overweight women, and 0.77 (95 % CI, 0.65, 0.91) in obese women. Preconception BMI also showed an interaction with the time of FA supplementation. Women with a normal BMI who began to take FA supplements in the preconception period had the lowest risk of PTD (aORs: 0.58 vs. 0.65 beginning in the first trimester). The aORs at preconception and the first trimester in the underweight group were 0.56 vs. 0.60. The aORs at preconception and the first trimester were 0.94 vs. 0.65 and 1.15 vs. 0.60 in the overweight and obesity groups, respectively. In our study, FA supplements reduced the risk of PTD, while abnormal BMI raised the risk of PTD, although higher BMI categories did not have this higher risk once adjusted analysis was conducted. The protective effect of FA supplementation for PTD was reduced in women with overweight or obesity. To get better protection of FA supplementation, women with normal BMI or underweight should begin to use in preconception, while women with overweight or obesity should begin to use after conception.

Background: Treacher Collins syndrome (TCS) is a rare autosomal dominant or recessive disorder, that involves unique bilateral craniofacial malformations. The phenotypes of TCS are extremely diverse. Interventional surgery can improve hearing loss and facial deformity in TCS patients.Method: We recruited seven TCS families. Variant screening in probands was performed by targeted next‐generation sequencing (NGS). The variants identified were confirmed by Sanger sequencing. The pathogenicity of all the mutations was evaluated using the guidelines of the American College of Medical Genetics and Genomics (ACMG) and InterVar software.Results: Three frameshift variants, two nonsense variants, one missense variant, and one splicing variant of TCOF1 were identified in the seven TCS probands. Five variants including c.1393C > T, c.4111 + 5G>C, c.1142delC, c.2285_2286delCT, and c.1719delG had not been previously reported. Furthermore, we report the c.149A > G variant for the first time in a Chinese TCS patient. We provided prenatal diagnosis for family 4. Proband 7 chose interventional surgery.Conclusion: We identified five novel variants in TCOF1 in Chinese patients with TCS, which expands the mutation spectrum of TCOF1 in TCS. Bone conduction hearing rehabilitation can improve hearing for TCS patients and prenatal diagnosis can provide fertility guidance for TCS families.

Methylmalonic acidemia (MMA)-affected patients may have developmental, hematological, neurological, metabolic, ophthalmological, and dermatological clinically abnormal findings. This study aimed to identify mutations in 13 Chinese MMA cases. We provided genetic counseling, treatment, and prenatal diagnosis for the families with MMA. Liquid chromatography-tandem mass spectrometry (LC–MS/MS) was performed and the results were confirmed by gas chromatography and mass spectrometry (GC/MS). Variant screening in probands was performed by targeted next-generation sequencing. Identified variants were confirmed by Sanger sequencing. Of these 13 MMA cases, seven were isolated MMA, and among them, six were caused by variants in MMUT and one was caused by a variant in MCEE. The other six cases were MMA with homocystinuria, which was caused by variants in MMACHC. We found six novel variants in three MMA-causing genes as follows: c.2008G>A, c.301_302insTA, c.984delC, and c.319A>T of MMUT; c.445T>C of MMACHC; and c.296T>C of MCEE. We provided prenatal diagnosis for two families with MMA at their next pregnancy, and one family had a healthy newborn. In conclusion, our findings expand the spectrum of genotypes in MMA. Effective genetic counseling is required to allow awareness of the patients’ families that MMA disease is treatable and a good prognosis can be obtained.

Background: Joubert syndrome (JBTS) is a rare genetic disorder that is characterized by midbrain‐hindbrain malformations. Multiple variants in genes that affect ciliary function contribute to the genetic and clinical heterogeneity of JBTS and its subtypes. However, the correlation between genotype and phenotype has not been elucidated due to the limited number of patients available.Methods: In this study, we observed different clinical features in two siblings from the same family. The older sibling was classified as a pure JBTS patient, whereas her younger sibling displayed oral‐facial‐digital defects and was therefore classified as an oral‐facial‐digital syndrome type VI (OFD VI) patient. Next, we performed human genetic tests to identify the potential pathogenic variants in the two siblings.Results: Genetic sequencing indicated that both siblings harbored compound heterozygous variants of a missense variant (c.1067C>T, p.S356F) and a frameshift variant (c.8377_8378del, p.E2793Lfs*24) in CPLANE1 (NM_023073.3).Conclusion: This study reports that two novel CPLANE1 variants are associated with the occurrence of JBTS and OFD VI. These results help elucidate the intrafamilial phenotypic variability associated with CPLANE1 variants.

Background:Epilepsy in childhood is a common and diverse neurological disorder. We conducted a genetic and phenotype analysis of a Chinese cohort of infants and children with epilepsy.Methods:We conducted a pedigree analysis of 260 Chinese patients with epilepsy onset during infancy or childhood by whole exome sequencing (WES).Results:Of the 260 probands analyzed, a genetic diagnosis was established in 135 patients. One-hundred eighty-eight phenotypes were detected in those 135 positive/likely positive patients, 106 patients had more than two phenotypes, and 67 patients had more than three phenotypes. A total of 142 variants of 81 genes were detected among the positive/likely positive patients. Among these 142 variants, of which 87 of 66 genes were novel.Conclusion:Our findings extend the variant spectrum of genes related to epilepsy. Our results will be useful for genetic testing and counseling for patients with epilepsy.