1 Introduction
Bardet-Biedl syndrome (BBS, OMIM 209900) is an autosomal recessive disease, caused by a variant of BBS-related genes. It was first described in 1920 by Dr. Georges Bardet. It is a non-motorized ciliary dysfunction that affects multiple systems. The prevalence of BBS is about 1/125,000∼1/160,000 with regional and ethnic differences (Moore et al., 2005; Tsang et al., 2018). A high incidence (around 1/13,500 newborns) among Arab Bedouins in the Arabian Peninsula, North African desert regions, and Newfoundland’s high blood isolation population is related to consanguineous marriage (Farag and Teebi, 1988; Farag and Teebi, 1989; Gouronc et al., 2020). It is characterized by retinitis pigmentosa, obesity, renal abnormalities, polydactyly, mental retardation, and hypogonadism. Other symptoms including ophthalmic diseases (e.g., astigmatism, strabismus, cataracts), hearing impairment, craniofacial congenital anomalies, hypoplastic teeth, toe deformity, short stature, asthma, neurological impairment (e.g., ataxia, hyperspasmia, olfactory abnormalities, behavioral and mental disorders, and poor coordination), digestive system abnormalities (e.g., intestinal atresia, imperforate anus, congenital megacolon, liver fibrillation), metabolic abnormalities (e.g., insulin resistance, hyperglycemia, dyslipidemia, hypothyroidism, hypertension), and cardiovascular abnormalities, have also been reported (Mujahid et al., 2018; Tsang et al., 2018; Guardiola et al., 2021; Zhong et al., 2023).
BBS is a ciliopathy and has been shown to be closely related to dysfunction of immotile cilia. To date, 28 genes have been reported to be associated with the BBS phenotypes, including 2 candidate genes (SCLT1 and SCAPER) and 2 contributors (NPHP1 and TTC21B) (Niederlova et al., 2019; Khan et al., 2023; Gnanasekaran et al., 2023). In comparison, pathogenic variants in the BBS genes involved in encoding the BBSome complex, including BBS1 (OMIM 209901), BBS2 (OMIM 606151), BBS4 (OMIM 600374), BBS5 (OMIM 603650), BBS7 (OMIM 607590), BBS8/TTC8 (OMIM 615985), and BBS9/PTHB1 (OMIM 607968), were the most common, followed by BBS genes involved in encoding BBSome complex “chaperone-like” proteins, including BBS6/MKKS (OMIM 604896), BBS10 (OMIM 610148), and BBS12 (OMIM 610683) (Seongjin et al., 2009; Dai et al., 2022; Melluso et al., 2023). BBS proteins are needed for the maintenance of ciliary structure and function. The BBSome complex is an essential component of cilia differentiation. It mediates the transport of proteins to the membrane structure of cilia and participates in their structure formation and function (Seongjin et al., 2009). BBSome complex chaperone-like proteins are involved in the regulation of the BBSome complex, which together with members of the Rab family of proteins to promote intraflagellar transport (Yan and Shen, 2022; Melluso et al., 2023). Molecular diagnosis can be clarified by genetic testing in about 80% of patients. Most studies reported that BBS1 and BBS10 are the most frequently implicated genes (Mujahid et al., 2018). However, still about 20% of patients currently do not have a definitive molecular diagnosis currently (Forsythe et al., 2018), presenting a significant challenge for diagnosis and genetic counseling.
We aim to highlight the genotype-phenotype relationship and the diagnosis of BBS by summering the BBS patients reported from China. Studies in Chinese and English from China were all reviewed.
2 Materials and methods
2.1 Data collection
According to the PRISMA guidelines, we reviewed the Wanfang and Weipu data in Chinese using “Bardet-Biedl syndrome”, “Laurence-Moon-Biedl syndrome”, “Laurence-Moon-Bardet-Biedl syndrome”, or “Polydactyly-Obesity-Renal-Ocular syndrome” and in Chinese or English, also above keyword and “China or Chinese” in PubMed up to December 2022. Only patients with detailed clinic feature data were involved in the following analysis.
2.2 Subjects
All papers and thesis were reviewed carefully. Laurence-Moon syndrome (OMIM 245800) together with BBS were previously regarded as one disease (named Laurence-Moon-Biedl syndrome or Laurence-Moon-Bardet-Biedl syndrome). Now, Laurence-Moon syndrome has been regarded as another disease. Hence, we removed Laurence-Moon syndrome patients. A total of 61 papers (Xu, 1991; Zhang et al., 1999; Lin et al., 2000; Shao et al., 2000; Shen et al., 2001; Li and Pang, 2003; Tong and Yu, 2003; Wang, 2003; Zhang and Hu, 2004; Zhou and Wang, 2005; Lei et al., 2006; Shou et al., 2006; Yang et al., 2006; Zhang et al., 2007a; Zhang et al., 2007b; Chen et al., 2007; Ke and An, 2007; Lin et al., 2007; Lu and Wang, 2007; Li et al., 2008a; Li et al., 2008b; Chen et al., 2008; Liang and Zhou, 2008; Liu et al., 2008; Si et al., 2008; Ye et al., 2008; Zhang et al., 2009; Shou et al., 2011; Xiao et al., 2011; Zheng et al., 2011; Zheng et al., 2012; Cheng et al., 2013; Jiang, 2013; Li et al., 2013; Lin and Zhang, 2014; Wang et al., 2014; Xia et al., 2014; Yi et al., 2014; Huang et al., 2015; Lou et al., 2015; Qi et al., 2015; Wu and Zhang, 2015; Chen et al., 2017; Li et al., 2017; Ding et al., 2018; Lin et al., 2018; Qu et al., 2018; Shen et al., 2018; Wang et al., 2018; Qiang et al., 2019; Tao et al., 2019; Wu et al., 2019; Li et al., 2020; Xie et al., 2021a; Liu et al., 2021; Li et al., 2022a; Li and Hu, 2022; Lu et al., 2022; Shao and Dong, 2022; Shen et al., 2022; Wei et al., 2022) , 4 thesis in Chinese (Han, 2011; Xin, 2014; Xiu, 2018; Li, 2021), and 24 English papers (Wu, 1956; Wei et al., 1998; Hou, 2004; Yang et al., 2008; Li et al., 2014; Xing et al., 2014; Qi et al., 2017; Li et al., 2019; Shen et al., 2019; Dan et al., 2020; Tao et al., 2020; Huang et al., 2021; Jing et al., 2021; Meng et al., 2021; Tang et al., 2021; Zhang et al., 2021; Li et al., 2022b; Cai et al., 2022; Dong et al., 2022; Shao et al., 2022; Tang et al., 2022; Tao et al., 2022; Yan et al., 2022) in PubMed from China were enrolled. Among these 96 papers and thesis, patients repeated in 6 papers were merged (Lei et al., 2006; Shou et al., 2006; Zhang et al., 2007a; Zhang et al., 2007b; Shou et al., 2011; Shao et al., 2022). Finally, a total of 153 patients with BBS were enrolled in this study. The special field of journals, profession of authors, demographic information, clinical data, and genotype was collected, and compared with previous reports. The description of variants were revised according to the ACMG guidelines.
2.3 Diagnostic criteria
In children, overweight and obesity were defined according to “Body mass index growth curves for Chinese children and adolescents aged 0–18 years” (Li et al., 2009a). In adults, overweight was defined as a BMI between 24.0 and 27.99 kg/m2 while obesity was defined as a BMI ≥28.00 kg/m2.
In children, hypertension was defined according to the “updating blood pressure references for Chinese children aged 3–17 years” (Fan et al., 2017). In adults, hypertension was defined as a diastolic blood pressure >90 mmHg and/or a systolic blood pressure >140 mmHg.
Hyperglycemia included impaired fasting glucose (fasting glucose 5.6–6.9 mmol/L) and impaired glucose tolerance (7.8–11.0 mmol/L). Diabetes was defined as fasting glucose ≥7.0 mmol/L and/or random blood glucose ≥11.1 mmol/L.
Short stature was defined according to the “height and weight standardized growth chats for Chinese children and adolescents aged 0–18 years” (Li et al., 2009b).
2.4 Statistical analysis
Statistical analyses were conducted using SPSS software (version 22). The Pearson’s chi-square test and Fisher’s exact test were used to measure enumeration data between subgroups. Quantitative data with a normal distribution were expressed as the means ± SDs and analyzed by the independent t-test. Quantitative data with skewed distributions were expressed as medians (minimums-maximums). Differences were considered statistically significant at p < 0.05.
4 Discussion
BBS is a main cause of syndromic forms of obesity although it is a rare disease. According to the prevalence (about 1/125,000∼1/160,000) reported (Moore et al., 2005; Tsang et al., 2018), these are currently about 10,000 patients in China (about 1.4 billion people) now. However, fewer than 150 patients have been reported to date. Moreover, most cases were reported from the Eastern region. This finding implied that misdiagnosis or miss diagnosis of BBS was common in China, especially in the Midwest region, although it may also be because of the non-register system of BBS in China.
Although it was an autosomal recessive disease, we noted that BBS was predominantly male with the male to female ratio of 1.64:1 (87/53). This result was similar to that in most other studies by Beales et al. (1999) (1.3:1) and Klein and Ammann (1969) (1.4:1), but the reason is still unclear. Whether this is associated with the fact that dysplasia of the vagina, uterus, and ovaries may be more apt to be ignored than cryptorchidism and micropenis needs further investigation. Although the age at diagnosis may be younger than those in other studies from Canada in 2005 (Moore et al., 2005) and the United Kingdom in 2018 (Mujahid et al., 2018), the mean age of these Chinese patients was 16.7 years old. This implies that the delayed diagnosis is still common. It was also notable that while only 15.68% of patients were reported by pediatricians, most (52.29%) were reported by ophthalmologists. In fact, polydactyly, a main feature and early clue of BBS, was noted in 85.62% of patients in this series. Hence, in addition to visual impairment, obesity, and genitourinary system abnormalities, BBS should be considered in infants (even fetuses) with polydactyly by pediatricians and pediatric surgeons.
The phenotype of BBS is heterogeneous. In our Chinese series, the incidences of visual impairment, polydactyly, obesity, genital anomalies, renal anomalies, and mental retardation were higher than those in most previous reports, although the age ass not older than those in previous reports (Beales et al., 1999; Moore et al., 2005; Mujahid et al., 2018). This implies that some atypical patients with few main clinical features may be misdiagnosis in China. It was notable that the incidence of some non-main clinical features (e.g., hearing loss, dental anomalies, anosmia/hyposmia, hydrometrocolpos, vaginal dysplasia, polycystic ovary syndrome in females) and complications (e.g., hypertriglyceridemia, hyperglycemia, diabetes millitus, and hypertension) were significantly lower than those in previous reports (Beales et al., 1999; Moore et al., 2005; Mujahid et al., 2018). These results suggest that careful evaluate of various deformities and congratulations on defects is needed for Chinese patients.
To date, 28 genes have been reported to be associated with BBS phenotypes (Niederlova et al., 2019; Gnanasekaran et al., 2023; Khan et al., 2023). Unlike Caucasian patients with higher proportions of BBS1 and BBS10 (Niederlova et al., 2019; Melluso et al., 2023), we noted that BBS7 was the prominent genotype, followed by BBS2, BBS10, BBS12, and BBS1 in these Chinese seies. This difference may imply the different genotype prominence in different geographic areas. This may also be associated with the fact that poor clinical diagnosis as BBS1 patients tend to have a milder pattern of disease (Niederlova et al., 2019; Guardiola et al., 2021). The analysis for the relationship between genotype and phenotype is difficult, as this rare disease. The BBSome chaperone-like protein is involved in the early synthesis of BBSome, so patients with BBS6/MKKS, BBS10, and BBS12 have more severe symptoms, especially BBS10 (Forsythe et al., 2017; Niederlova et al., 2019). Moreover, patients with BBS2 were reported to have severe symptoms (Florea et al., 2021). The proportion of renal abnormalities in patients with BBS7 types is relatively high (>60%) and relatively lower in BBS2 and BBS10 types (Niederlova et al., 2019; Florea et al., 2021). Patients with BBS2 and BBS4 types have a higher proportion of polydactyly (Niederlova et al., 2019), and BBS10 and BBS12 types are apt to obese (Forsythe and Beales, 2013; Dai et al., 2022; Melluso et al., 2023). We noted that BBS7 had higher penetrance. BBS2 had higher hearing impairment and lower renal abnormality penetrance. BBS10 had higher penetrance except for the lower enal abnormality. It was notable that hearing impairment was reported in BBS2, but not in BBS7 and BBS10. The relationship between genotype and phenotype must be observed with a larger sample size.
The diagnosis of BBS is some difficult due to the heterogeneity of phenotypes. Beales et al. (1999) summarized and amended that BBS clinical diagnosis should meet 4 major symptoms, or 3 major symptoms and 2 secondary symptoms. Fortunately, genetic diagnosis has been improved in recent years in China, and 89 patients had comfirmed diagnosis and genotyping by sequencing in recent years. Unlike reports from the United States (Guardiola et al., 2021), the variant sites are more dispersed in our Chinese series. As most patients have point variants, sequencing, but not karyotype and array comparative genomic hybridization (aCGH), is suggested as the first line genetic analysis. Moreover, we also used next-generation sequencing for newborn screening in China, which may improve the early diagnosis for some rare genetic diseases (Tong et al., 2022).
The diagnosis of BBS based on prenatal findings is still some difficult, as it cannot identify visual impairment, learning difficulties, or obesity in utero. Fortunately, prenatal diagnosis war comfirmed by sequencing for 10 fetuses after renal anomalies and/or polydactyly found by ultrasound in the past 4 years. Hence, in fetuses with genitourinary abnormalities, polydactyly, and/or hydrometrocolpos, BBS should be considered. Further careful evaluation for various deformities and genomic sequencing should be suggested.
Genetic counseling for the family of the proband is needed. As BBS is an autosomal recessive disease, consanguineous marriage should be avoided. The consanguinity rate in our series was 17.65%, which was lower than that in other studies by Beales et al. (1999) (39%) and Klein and Ammann (1969) (48%), and may be associated with more dispersed variant sites in our series. However, this reflected the lack of awareness of the dangers of consanguineous marriage in these Chinese families.
There is still no specific treatment for BBS. Congenital structural abnormalities (e.g., digestive tract abnormalities), obesity and metabolic syndrome, chronic kidney disease, and retinitis pigmentosa are the main influencing factors for the quality of life and longevity of BBS patients. Congenital structural abnormality correction, diet and lifestyle interventions to prevent obesity and metabolic syndrome, relieve chronic kidney disease, and slow down the retinitis pigmentosa progression are important for BBS patients. Drugs (e.g., setmelanotide) for the obesity (Tauber, 2022; Forsythe et al., 2023), and gene therapy for retinitis pigmentosa are in clinical trails (Xie et al., 2021b; Hsu et al., 2023).
There were several limitations. First, some patients were reported having “Laurence-Moon-Biedl syndrome” or “Laurence-Moon-Bardet-Biedl syndrome”. It may not be accurate to exclude some patients without genetic analysis data. Second, as a review analysis, some clinical data of some patients were not provided. Moreover, genetic analysis was not performed in all patients, and most patients reported before 2017 years. Hence, the genotype-phenotype relationship analysis may not be accurate.
In summary, misdiagnosis or miss diagnosis of BBS may be common in China. In patients with polydactyly, visual impairment, obesity, renal abnormalities, hypogonadism, and mental retardation, or in fetuses with polydactyly and/or renal abnormalities, BBS should be considered in the differential diagnosis. Other deformities should be evaluated carefully and genetic analysis should be performed as early as possible.