The pathogenic mechanism of syndactyly type V identified in a Hoxd13Q50R knock-in mice.

Syndactyly type V (SDTY5) is an autosomal dominant extremity malformation characterized by fusion of the fourth and fifth metacarpals. In the previous publication, we first identified a heterozygous missense mutation Q50R in homeobox domain (HD) of HOXD13 in a large Chinese family with SDTY5. In order to substantiate the pathogenicity of the variant and elucidate the underlying pathogenic mechanism causing limb malformation, transcription-activator-like effector nucleases (TALEN) was employed to generate a Hoxd13Q50R mutant mouse. The mutant mice exhibited obvious limb malformations including slight brachydactyly and partial syndactyly between digits 2-4 in the heterozygotes, and severe syndactyly, brachydactyly and polydactyly in homozygotes. Focusing on BMP2 and SHH/GREM1/AER-FGF epithelial mesenchymal (e-m) feedback, a crucial signal pathway for limb development, we found the ectopically expressed Shh, Grem1 and Fgf8 and down-regulated Bmp2 in the embryonic limb bud at E10.5 to E12.5. A transcriptome sequencing analysis was conducted on limb buds (LBs) at E11.5, revealing 31 genes that exhibited notable disparities in mRNA level between the Hoxd13Q50R homozygotes and the wild-type. These genes are known to be involved in various processes such as limb development, cell proliferation, migration, and apoptosis. Our findings indicate that the ectopic expression of Shh and Fgf8, in conjunction with the down-regulation of Bmp2, results in a failure of patterning along both the anterior-posterior and proximal-distal axes, as well as a decrease in interdigital programmed cell death (PCD). This cascade ultimately leads to the development of syndactyly and brachydactyly in heterozygous mice, and severe limb malformations in homozygous mice. These findings suggest that abnormal expression of SHH, FGF8, and BMP2 induced by HOXD13Q50R may be responsible for the manifestation of human SDTY5.

A novel homozygous missense variant in LRP4 causing Cenani-Lenz syndactyly syndrome and literature review.

BACKGROUND: Cenani-Lenzsyndactyly syndrome (CLSS; OMIM 212780) is a rare autosomal recessive acral deformity, which is mainly manifested in the fusion of fingers or toes, disordered phalangeal structure, shortening or fusion of the radius and ulna, and renal hypoplasia. CASE PRESENTATION: Our report described an individual with mild phenotypes from China. His parents were not consanguineous. The affected individual was non-dysmorphic. Standard X-ray showed that the both hands have only four metacarpal bones. The distal end of the first metacarpal bone on the right was relatively slender, and the distal phalanx was absent. Multiple phalanges and some soft tissues of both hands were fused. Exome sequencing revealed a novel biallelic c.282C⟩Avariant in low-density lipoprotein receptor-related protein 4 (LRP4; OMIM604270; NM_002334.4) causing p. (Asn94Lys) change in the encoded protein. This variant is predicted to be potentially pathogenic, affecting protein structure and function. CONCLUSION: We report a novel missense variant present in homozygosity in LRP4 to broaden the pathogenic spectrum of LRP4 in syndactyly, and exome sequencing technology is a powerful tool for genetic analysis in prenatal diagnosis and medical research, as a preferred method for the diagnosis of syndactyly and related phenotypes.

A Japanese patient with Teebi hypertelorism syndrome and a novel CDH11 EC1 domain variant.

The gene CDH11 encodes cadherin-11, a Type II cadherin superfamily member that contains five extracellular cadherin (EC) domains. Cadherin-11 undergoes trans-dimerization via the EC1 domain to generate cadherin complexes. Compound heterozygous and homozygous loss-of-function CDH11 variants are observed in Elsahy-Waters syndrome (EWS), which shows characteristic craniofacial features, vertebral abnormalities, cutaneous syndactyly in 2-3 digits, genitourinary anomalies, and intellectual disability. Heterozygous CDH11 variants can cause Teebi hypertelorism syndrome (THS), which features widely spaced eyes and hypospadias. We report a THS patient with a novel CDH11 variant involving the EC1 domain. The patient was a 10-month-old male with normal developmental milestones, but had widely spaced eyes, strabismus, hypospadias, shawl scrotum, broad thumbs (right bifid thumb in x-ray), polysyndactyly of the left fourth finger, and cutaneous syndactyly of left third/fourth fingers. Exome sequencing identified a de novo heterozygous CDH11 variant (NM_001797.4:c.229C > T [p.Leu77Phe] NC_000016.9:g.64998856G > A). Clinical features were consistent with previously reported THS patients, but polysyndactyly, broad thumb, and cutaneous syndactyly overlapped phenotypic features of EWS. THS and EWS may represent a spectrum of CDH11-related disorders. Residue Leu77 in this novel CDH11 variant lines a large hydrophobic pocket where side chains of the partner cadherin-11 insert to trans-dimerize, suggesting that the cadherin-11 structure might be altered in this variant.

LRP4 site-specific variants in the third ß-propeller domain causes congenital myasthenic syndrome type 17.

LRP4 is expressed in many organs. It mediates SOST-dependent inhibition of bone formation and acts as an inhibitor of WNT signaling. It is also a postsynaptic end plate cell surface receptor at the neuromuscular junction and is central to its development, maintenance, and function. Pathogenic variants of LRP4 that specifically affect the canonical WNT signaling pathway are known to be associated with Cenani-Lenz syndactyly syndrome or the overlapping condition sclerosteosis. However, site-specific pathogenic variants of LRP4 have been associated with the congenital myasthenic syndrome (CMS) type 17 with no abnormal bone phenotype. Only two studies reported biallelic variants of LRP4 associated with CMS17 that presented during childhood. All three reported variants (NM_002334.4: p.Glu1233Ala, p.Glu1233Lys, or p.Arg1277His) are located within the 3'-edge of the third ß-propeller domain of LRP4. We report on a patient with a biallelic variant of the LRP4 gene presenting with a severe and neonatal lethal phenotype; we also provide a literature review of the previously reported patients. A female neonate, born to healthy consanguineous parents, presented with severe hypotonia, congenital diaphragmatic hernia, pulmonary hypertension, and progressive hypoxemia. Two of her siblings presented with a similar condition in the past, and all three died shortly after birth. Clinical exome sequencing revealed homozygosity for the pathogenic variant NM_002334.4:c.3698A > C (p.[Glu1233Ala]).

Thurston syndrome with thalassaemia: a rare case devising a novel molecular and phenotypic variation.

A male infant presented with progressive paleness of the body since 3 months of age. On examination, the child had pallor, microcephaly with dysmorphic facies (depressed nasal bridge, low set ears, retrognathia, high arched palate and tongue hamartoma). Postaxial polydactyly in bilateral hands and feet, broad great toes, with syndactyly of left fourth and fifth toes were present. The haemogram showed severe anaemia with a microcytic hypochromic picture. High-performance liquid chromatography (HPLC) was normal. However, the parents' HPLC was suggestive of beta thalassaemia trait. Whole-exome sequencing revealed Thurston syndrome with beta-thalassaemia in homozygous pattern with a novel mutation. It is a rare genetic syndrome exclusively found in the South Asian population. Due to the rarity, identification of this syndrome is often difficult and requires awareness among clinicians. However, it is important to diagnose the disorder accurately in order to provide appropriate genetic counselling and prognostication to the parents.

A Recurrent Nonsense Mutation in NECTIN4 Underlying Ectodermal Dysplasia-Syndactyly Syndrome with a Novel Phenotype in a Consanguineous Kashmiri Family.

EDSS1, a syndrome characterized by ectodermal dysplasia-syndactyly, is inherited in an autosomal recessive manner due to mutations in the NECTIN4/PVRL4 gene. Clinical manifestations of the syndrome include defective nail plate, sparse to absent scalp and body hair, spaced teeth with enamel hypoplasia, and bilateral cutaneous syndactyly in the fingers and toes. Here, we report a consanguineous family of Kashmiri origin presenting features of EDSS1. Using whole exome sequencing, we found a recurrent nonsense mutation (NM_030916: c.181C > T, p.(Gln61 ∗)) in the NECTIN4 gene. The variant segregated perfectly with the disorder within the family. The candidate variant was absent in 50 in-house exomes pertaining to other disorders from the same population. In addition to the previously reported clinical phenotype, an upper lip cleft was found in one of the affected members as a novel phenotype that is not reported by previous studies in EDSS1 patients. Therefore, the study presented here, which was conducted on the Kashmiri population, is the first to document a NECTIN4 mutation associated with the upper lip cleft as a novel phenotype. This finding broadens the molecular and phenotypic spectrum of EDSS1.

HOXD13-associated synpolydactyly: Extending and validating the genotypic and phenotypic spectrum with 38 new and 49 published families.

PURPOSE: HOXD13 is an important regulator of limb development. Pathogenic variants in HOXD13 cause synpolydactyly type 1 (SPD1). How different types and positions of HOXD13 variants contribute to genotype-phenotype correlations, penetrance, and expressivity of SPD1 remains elusive. Here, we present a novel cohort and a literature review to elucidate HOXD13 phenotype-genotype correlations. METHODS: Patients with limb anomalies suggestive of SPD1 were selected for analysis of HOXD13 by Sanger sequencing, repeat length analysis, and next-generation sequencing. Literature was reviewed for HOXD13 heterozygotes. Variants were annotated for phenotypic data. Severity was calculated, and cluster and decision-tree analyses were performed. RESULTS: We identified 98 affected members of 38 families featuring 11 different (likely) causative variants and 4 variants of uncertain significance. The most frequent (25/38) were alanine repeat expansions. Phenotypes ranged from unaffected heterozygotes to severe osseous synpolydactyly, with intra- and inter-familial heterogeneity and asymmetry. A literature review provided 160 evaluable affected members of 49 families with SPD1. Computer-aided analysis only corroborated a positive correlation between alanine repeat length and phenotype severity. CONCLUSION: Our findings support that HOXD13-protein condensation in addition to haploinsufficiency is the molecular pathomechanism of SPD1. Our data may, also, facilitate the interpretation of synpolydactyly radiographs by future automated tools.

Same Gene, Different Story (a Case Report of Congenital Long QT Syndrome Subtype 8 With a Novel Mutation).

Long QT syndrome (LQTS) 8 is a rare inherited channelopathy caused by CACNA1C gene mutations that affects calcium channels, and when combined with congenital heart defects, musculoskeletal defects, and neurodevelopmental defects, it is referred to as Timothy syndrome. A female patient, aged 17 years, presented with a witnessed episode of syncope secondary to ventricular fibrillation that was successfully cardioverted. Electrocardiogram showed sinus bradycardia 52/min, normal axis, and a QTc of 626 ms. In the hospital, she had another episode of asystole and Torsade de pointes and underwent successful cardiopulmonary resuscitation. Echocardiogram showed severely reduced left ventricular systolic function from postcardiac arrest myocardial dysfunction and no congenital heart defects. Long QT genetic test detected a missense mutation in the CACNA1C gene (NM_199460.3, variant c.2573G>A, p Arg858His, heterozygous, autosomal dominant), resulting in replacement of arginine with histidine at position 858(R858H), leading to the gain of function in the L-type calcium channel. Given the absence of congenital cardiac defects, musculoskeletal deformities, or neurodevelopmental delay a final diagnosis of LQTS subtype 8 was made. A cardioverter defibrillator was implanted. In conclusion, our case highlights the importance of genetic testing in the diagnosis of LQTS. Some CACNA1C mutations, such as R858H described here, cause LQTS without the extracardiac manifestations observed in classic Timothy syndrome and should be included in the genetic testing for LQTS. To the best of our knowledge, our case is the first one from United States with the R585H mutation. Three cases with similar mutations have been reported from Japan and one from New Zealand.

A novel homozygous nonsense mutation in NECTIN4 gene in a Pakistani family with ectodermal dysplasia syndactyly syndrome 1.

BACKGROUND: Ectodermal dysplasia syndactyly syndrome 1 (EDSS1) is a rare hereditary disorder characterized by defects in teeth, hair, and nails in association with a fusion of the digits. Genetically, the disease phenotypes are caused by homozygous and compound heterozygous variants in NECTIN4 gene. OBJECTIVE: The main objective of the study was to identify the pathogenic sequence variant(s) for family screening and identification of carriers. METHODS: In the present study, the authors have investigated a large consanguineous family of Pakistani origin segregating autosomal recessive EDSS1. All the coding exons of the NECTIN4 gene were directly sequenced using gene-specific primers. RESULTS: The affected individuals presented the classical EDSS1 clinical features including sparse hair, hypoplastic nails with thick flat discolored nail plates, peg-shaped, conical, and widely spaced teeth with enamel hypoplasia, proximal cutaneous syndactyly of fingers and toes. Sequence analysis of the coding region of the NECTIN4 identified a novel nonsense variant [c.163C>T; p.(Arg55*)] in exon-2 of the gene. Computational analysis of protein structure revealed that the variant induced premature termination at Arg55 located in Ig-like V-loop region leading to loss of Ig-C2 type domains and transmembrane region, and most likely Nectin-4 function will be lost. STUDY LIMITATION: Gene expression studies are absent that would have strengthened the findings of computational analysis. CONCLUSION: The present study expanded the phenotypic and mutation spectrum of the NECTIN4 gene. Further, the study would assist in carrier testing and prenatal diagnosis of the affected families.

A novel Hoxd13 mutation causes synpolydactyly and promotes osteoclast differentiation by regulating pSmad5/p65/c-Fos/Rank axis.

The mutations of HOXD13 gene have been involved in synpolydactyly (SPD), and the polyalanine extension mutation of Hoxd13 gene could lead to SPD in mice. In this study, a novel missense mutation of Hoxd13 (NM_000523: exon2: c.G917T: p.R306L) was identified in a Chinese family with SPD. The mice carrying the corresponding Hoxd13mutation were generated. The results showed that the homozygous mutation of Hoxd13 also caused SPD, but heterozygous mutation did not affect limbs development, which was different from that of SPD patients. With the increasing generation, the mice with homozygous Hoxd13 mutation presented more severe syndactyly. Western blotting showed that this mutation did not affect the protein expression of Hoxd13, suggesting that this mutation did not result in haploinsufficiency. Further analysis demonstrated that this homozygous Hoxd13mutation promoted osteoclast differentiation and bone loss, and enhanced the mRNA and protein expression of osteoclast-related genes Rank, c-Fos, and p65. Meanwhile, this homozygous Hoxd13 mutation elevated the level of phosphorylated Smad5 (pSmad5). Co-immunoprecipitation verified that this mutation attenuated the interaction between pSmad5 and HOXD13, suggesting that this mutation released more pSmad5. Inhibition of pSmad5 reduced the expression of Rank, c-Fos, and p65 despite in the mutation group. In addition, inhibition of pSmad5 repressed the osteoclast differentiation. ChIP assay confirmed that p65 and c-Fos could bind to the promoter of Rank. These results suggested that this novel Hoxd13 mutation promoted osteoclast differentiation by regulating Smad5/p65/c-Fos/Rank axis, which might provide a new insight into SPD development.

FREM2-related Fraser syndrome with popliteal pterygium and structural central nervous system anomalies.

Fraser syndrome (FS) is a rare multiple malformation disorder characterized by cryptophthalmos, characteristic craniofacial dysmorphism, cutaneous syndactyly, malformations of the respiratory and urinary tract, and anogenital anomalies. Although the characteristic presentation of FS can be detected prenatally, oligohydramnios often challenges the clinical diagnosis. Here we report on the atypical prenatal and postmortem findings of a fetus with FS caused by a novel homozygous frameshift variant in FREM2. Our study highlights the variable manifestations of the FS and expands the clinical spectrum to include popliteal pterygium and structural central nervous system anomalies.

Genomic sequencing in a cohort of individuals with fibular aplasia, tibial campomelia, and oligosyndactyly (FATCO) syndrome.

Fibular aplasia, tibial campomelia, and oligosyndactyly (FATCO) syndrome (MIM 246570) is a rare disorder characterized by specific skeletal findings (fibular aplasia, shortened or bowed tibia, and oligosyndactyly of the foot and/or hand). Typically, no other anomalies, craniofacial dysmorphism, or developmental delays are associated. Here we report three unrelated individuals with limb anomalies consistent with FATCO syndrome who have been followed clinically for 5 years. Genetic testing of previously reported individuals with FATCO syndrome has not revealed a genetic diagnosis. However, no broader sequencing approaches have been reported. We describe the results of the three individuals with FATCO syndrome from exome and genome sequencing, all of which was nondiagnostic. Our study suggests that FATCO syndrome is not the result of a simple monogenic etiology.

The genetic factors contributing to the risk of cleft lip-cleft palate and their clinical utility.

Cleft lip and cleft palate (CL/P) are among the most common congenital malformations in neonates and have syndromic or nonsyndromic forms. Nonsyndromic forms of malformation are being reported to be associated with chromosomal DNA modification by teratogenic exposure and to complex genetic contributions of multiple genes. Syndromic forms are shown to be related to chromosomal aberrations or monogenic diseases. There is a growing body of data illustrating the association of several genes with risk of developing this malformation, including genetic defects in T-box transcription factor-22 (TBX22), interferon regulatory factor-6 (IRF6), and poliovirus receptor-like-1 (PVRL1), responsible for X-linked cleft palate, cleft lip/palate-ectodermal dysplasia syndrome, and Van der Woude and popliteal pterygium syndromes, respectively. Genetic variants in MTR, PCYT1A, ASS1, SLC 25A13, GSTM1, GSTT1, SUMO1 BHMT1, and BHMT2 are being reported to be linked with CL/P risk. The etiology of nonsyndromic CLP is still remained to be unknown, although mutations in candidate genes have been found. Here, we provide an overview about the potential variants to be associated with CL/P for identification of the relative risk of CLP with respect to the basis of genetic background and environmental factors (e.g., dietary factors, alcohol use).

The identification of a novel CCNQ gene tail extension variant contributing to syndactyly, telecanthus and anogenital and renal malformations syndrome.

The "toe syndactyly, telecanthus and anogenital and renal malformations" (STAR) syndrome is a rare X-linked dominant inherited kidney ciliopathy caused by CCNQ gene mutations. Here, we investigated the genotype and phenotype in the first two twin sisters with a novel tail extension CCNQ variant in Asia. Genetic variants of the pedigree were screened using whole-exome sequence analysis and validated by direct Sanger sequencing. The genetic function was investigated through cultured cells and zebrafish embryos transfected with mutant. The proband is suffered from end-stage renal disease, telecanthus, scoliosis, anal atresia, bilateral hydronephrosis pyeloureter dilation and hearing loss, while her twin sister had milder phenotypes. A novel heterozygous variant c.502_518delinsA (p.Val168SerfsTer173) in CCNQ gene was identified in the twins and their asymptomatic mosaic mother. The concurrent deletion of 17 bases and insertion of one base variant led to the loss of 5 amino acids, subsequently caused a 96 more amino acids tail extension delaying the appearance of stop codon. The loss-of-function variant of CCNQ not only led to the impaired expression of cyclin M but also increased the binding affinity of CDK10-cyclin M complex, which is different from the previous study. The research expanded the genotypic and phenotypic spectrum of STAR syndrome.

A novel variant in AFF3 underlying isolated syndactyly.

Isolated syndactyly is a common limb malformation with limited known genetic etiology. We used exome sequencing to discover a novel heterozygous missense variant c.2915G > C: p.Arg972Pro in AFF3 on chromosome 2q11.2 in a family with isolated syndactyly in hands and feet. AFF3 belongs to a family of nuclear transcription activating factors and is involved in limb dorsoventral patterning. The variant Arg972Pro is located near the C terminus, a region that is yet to be associated with human disorders. Functional studies did not show a difference in the stability or subcellular localization of the mutant and wild type proteins. Instead, overexpression in zebrafish embryos suggests that Arg972Pro is a loss-of-function allele. These results suggest that variants in the C terminus of AFF3 may cause a phenotype distinct from previously characterized AFF3 variants.

ERI1: A case report of an autosomal recessive syndrome associated with developmental delay and distal limb abnormalities.

ERI1 is an evolutionary conserved 3'-5' exonuclease with an important function in multiple RNA processing pathways. Although the molecular mechanisms in which ERI1 is involved have been studied extensively in model organisms, the pathology associated with ERI1 variants in humans has remained elusive because no case has been reported so far. Here, we present a case of a female patient with a homozygous nonsense variant in ERI1 gene. The patient exhibits mild intellectual disability, eyelid ptosis, and anomalies in her hands and feet (brachydactyly, clinodactyly, dysplastic/short nail of halluces, brachytelephalangy, short metacarpals, and toe syndactyly). This case report is the first of its kind and is invaluable for understanding ERI1 pathology in humans.

Increased CaV1.2 late current by a CACNA1C p.R412M variant causes an atypical Timothy syndrome without syndactyly.

Timothy syndrome (TS) is a rare pleiotropic disorder associated with long QT syndrome, syndactyly, dysmorphic features, and neurological symptoms. Several variants in exon 8 or 8a of CACNA1C, a gene encoding the α-subunit of voltage-gated Ca2+ channels (Cav1.2), are known to cause classical TS. We identified a p.R412M (exon 9) variant in an atypical TS case. The aim of this study was to examine the functional effects of CACNA1C p.R412M on CaV1.2 in comparison with those of p.G406R. The index patient was a 2-month-old female infant who suffered from a cardio-pulmonary arrest in association with prolonged QT intervals. She showed dysmorphic facial features and developmental delay, but not syndactyly. Interestingly, she also presented recurrent seizures from 4 months. Genetic tests identified a novel heterozygous CACNA1C variant, p.R412M. Using heterologous expression system with HEK-293 cells, analyses with whole-cell patch-clamp technique revealed that p.R412M caused late Ca2+ currents by significantly delaying CaV1.2 channel inactivation, consistent with the underlying mechanisms of classical TS. A novel CACNA1C variant, p.R412M, was found to be associated with atypical TS through the same mechanism as p.G406R, the variant responsible for classical TS.

Triphalangeal thump, thumb duplication, and syndactyly: The first case report in the literature.

RATIONALE: Triphalangeal thumb (TPT) is a rare congenital malformation where the thumb has three phalanges instead of two. Syndactyly is a condition in which children are born with fused or webbed fingers. The combination of TPT, Syndactyly, and thumb duplication is extremely rare, especially when these deformities are combined in one hand. PATIENT CONCERNS: Hand abnormalities and polydactyl have been reported in a 1-year-old boy. DIAGNOSIS: A clinical examination reveals two thumb duplications, finger fusion (Syndactyly), and a thumb with three phalanges (TPT). The diagnosis was based on clinical findings and an X-ray image of the hand. INTERVENTIONS: The Z-plasty method was used to remove the adhesion between the thumb and forefinger, as well as the removal of the medial and distal phalanx of the thumb's medial tip. OUTCOMES: The patient was followed for 2 months and found him in good health. To authors' knowledge, we described an unusual case from Syria, considered the first in medical history. LESSONS LEARNED: General and plastic surgeons should be aware about this unusual mix of the three abnormalities. The family history must also be carefully investigated to explore the occurrence of hereditary illnesses.

Identification of a HOXD13 variant in a Mongolian family with incomplete penetrance syndactyly by exon sequencing.

BACKGROUND: Syndactyly (SD) refers to a deformity caused by the fusion and limb differentiation disorder of soft tissues and/or skeletons to varying extents between adjacent fingers (toes). The main features of this disease are phenotypic heterogeneity and genetic heterogeneity. In this study, we examined four generations of a Chinese Mongolian with different phenotypes of syndactylia and analysed and identified the pathogenic genetic variants of SD by exon sequencing. METHODS: The clinical phenotypes of patients were analysed, and the hands and feet were examined by X-ray. The pedigree was drawn, and the family data were analysed. Peripheral blood was collected from the family members, and genomic DNA was extracted. The candidate genes of SD were identified by exon sequencing, and the mutation sites of the captured candidate genes were amplified by PCR and verified by Sanger sequencing. RESULTS: The family has congenital syndactyly, which is an autosomal dominant disease. At present, this condition has been passed down for 4 generations and was identified in 9 patients, including 4 males and 5 females. Five patients, I2, II4, III5, III,7 and III10, had unilateral syndactyly, and four patients, III16, IV3, IV6 and IV7, had bilateral finger syndactyly. All of their toes were unaffected. The proband and the other patients in this family had a c.917G > A (p.R306Q) mutation, which is located at position 917 of the second exon of the HOXD13 gene. This mutation results in a change in the amino acid at position 306, in which arginine is changed to glutamine. This mutation cosegregates in unaffected individuals and affected patients in this family. Moreover, 201 Mongolian genome databases and a thousand human genome databases were referenced to further confirm that the pathogenic genetic variant that causes syndactyly in this family is found in HOXD13. CONCLUSION: This study found that the mutation site of the pathogenic gene in this family was HOXD13, c.917G > A (p.R306Q). The phenotype of the family member III12 was normal, but this member was also a carrier of the pathogenic genetic variant. This indicates that the disease of this family has incomplete penetrance characteristics. Our results further enrich the expression profile of the HOXD13 gene.