Short Communication
Prenatal diagnosis of recurrent autosomal dominant
osteogenesis imperfecta
associated with unaffected parents and paternal gonadal mosaicism
Chih-Ping Chen a,b,c,d,e,f,g *, Shuan-Pei Lin b,c,h.i, Yi-Ning Su j, Schu-Rern Chern b, Jun-Wei Su a,k, Wayseen Wang b,l
a Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei, Taiwan b Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan
c Department of Medicine, Mackay Medical College, New Taipei City, Taiwan d Department of Biotechnology, Asia University, Taichung, Taiwan
e School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan f Institute of Clinical and Community Health Nursing, National Yang-Ming University, Taipei, Taiwan g Department of Obstetrics and Gynecology, School of Medicine, National Yang-Ming University, Taipei,
Taiwan
h Department of Pediatrics, Mackay Memorial Hospital, Taipei, Taiwan i Mackay Medicine, Nursing and Management College, Taipei, Taiwan
j Department of Obstetrics and Gynecology, School of Medicine, College of Medicine, Taipei Medical
University, Taipei, Taiwan
k Department of Obstetrics and Gynecology, China Medical University Hospital, Taichung, Taiwan l Department of Bioengineering, Tatung University, Taipei, Taiwan
* Correspondence to: Chih-Ping Chen, MD
Department of Obstetrics and Gynecology, Mackay Memorial Hospital 92, Section 2, Chung-Shan North Road, Taipei, Taiwan
Tel: +886-2-25433535; Fax: +886-2-25433642, +886-2-25232448 E-mail: [email protected]
Abstract
Objective: To present prenatal diagnosis of recurrent autosomal dominant osteogenesis imperfecta (OI) associated with unaffected parents and paternal gonadal mosaicism.
Materials, methods and results: A 37-year-old woman was referred for genetic counseling at 18 weeks of gestation because of advanced maternal age and a family history of OI. The woman had a daughter who was affected with OI type III and carried an insertion frameshift mutation of c.4308_4309insA in exon 52 of the COL1A1 gene. The woman and her husband were non-consanguineous and healthy. Amniocentesis was performed at 18 weeks of gestation. Cytegenetic analysis revealed a karyotype of 46,XX. Molecular analysis of the amniocytes revealed a recurrent mutation of c.4308_4309insA in exon 52 of the COL1A1 gene. Mutational analysis of the family revealed no mutation of the COL1A1 gene in the parental bloods. However, mosaicism for the COL1A1 mutation was found in the paternal sperms. Level II ultrasound examination showed curved right tibia, a narrow chest with irregular ribs and mild frontal bossing in the fetus. The parents decided to terminate the pregnancy, and a female fetus was delivered at 23 weeks of gestation with curved long bones.
Conclusion: Recurrent autosomal dominant OI may occur in the offspring of unaffected parents with parental gonadal mosaicism. Genetic counseling of recurrent autosomal dominant OI should include a thorough mutational analysis of the family members, and mutational analysis of the sperms may detect paternal gonadal mosaicism for the mutation.
Introduction
Osteogenesis imperfecta (OI) is a heterogeneous heritable disorder that involves connective tissues and is characterized by bone fragility, decreased bone mass and other connective-tissue manifestations such as blue sclerae, hyperlaxity of skin and ligaments, dentinogenesis imperfecta (DI) and hearing loss [1,2]. OI occurs in approximately 1:20,000-1:60,000 births [3,4]. Here, we report identification an insertion frameshift mutation of c.4308_4309insA in exon 52 of the COL1A1 gene in a 1½-year-old girl with OI type III and in a fetus with recurrent autosomal dominant OI in a family with unaffected parents and paternal gonadal mosaicism.
Materials, Methods and Results
A 37-year-old, gravida 4, para 3, woman was referred for genetic counseling at 18 weeks of gestation because of advanced maternal age and a family history of having a daughter affected with OI type III. The 1½-year-old daughter was the woman’s second child of her second marriage with a 44-year-old husband. The woman and her husband were non-consanguineous and healthy. The couple’s eldest 3-year-old son was healthy. The mother’s other two children of the previous marriage were all healthy. Their affected daughter was delivered vaginally at 38 weeks of gestation after an uncomplicated pregnancy with a body weight of 2,800 g (15th centile) and a length of 48.5 cm (15th centile). Prenatal ultrasound findings were unremarkable. Immediately after birth, she was noted to have paralysis of upper limbs. Shoulder dislocation or subluxation, birth trauma of the bones, brachial plexus injury and clavicle fractures were all suspected. During admission, X-rays showed healed fractures in right humerus, left ulna and radius, bilateral femurs and bilateral ribs, and a new fracture in left humerus. Her condition stabilized after parenteral bisphosphonate therapy. Over the next 1½ years, she had suffered from repeated fractures of the extremities after minimal traumas. The clinical findings were consistent with the diagnosis of OI type III. On examination, she had mild scoliosis, blue sclerae and DI but no hearing loss. Molecular analysis of type I collagen genes revealed an insertion frameshift mutation of c.4308_4309insA in exon 52 of the COL1A1 gene (Fig. 1). During this pregnancy, amniocentesis was performed at 18 weeks of gestation. Cytegenetic analysis of the amniocytes revealed a
c.4308_4309insA in exon 52 of the COL1A1 gene (Fig. 2). Mutational analysis of the parental bloods did not find such a mutation (Fig. 2). However, Molecular analysis of the sperm DNA derived from the father revealed mosaicism for a mutation of c.4308_4309insA in exon 52 of the COL1A1 gene (Fig. 2). Level II ultrasound examination of the fetus showed curved right tibia, a narrow chest with irregular ribs and mild frontal bossing. The parents decided to terminate the pregnancy, and a 624-g female fetus was delivered at 23 weeks of gestation with curved long bones.
Discussion
To date, at least 12 types of OI have been identified, and approximately 90% of the patients of OI have dominant mutations in the COL1A1 gene (OMIM 120150) encoding 1 type I collagen chain and in the COL1A2 gene (OMIM 120160) encoding 2 type I collagen chain [5]. OI type I is associated with mutations in COL1A1 mostly because of a null allele caused by a premature stop codon due to deletions, duplications, nonsense mutations and frameshift mutations [6,7]. OI type II ~ type IV are associated with mutations in COL1A1 or COL1A2 most commonly due to glycine substitutions and less frequently due to splicing defects, deletions, insertions or duplications [8-11]. OI type I ~ type V are inherited in an autosomal dominant pattern. OI type VI ~ type XII are inherited in an autosomal recessive pattern and can be caused by homozygous or compound heterozygous mutations in the genes of FKBP10, CRTAP, LEPRE1, PPIB, SERPINH2, SP7 and SERPINF1, respectively.
The present case provides evidence that an insertion mutation of c.4308_4309insA in exon 52 of the COL1A1 gene can result in OI but not a lethal outcome. This insertion mutation causes a frameshift and predicts p.Leu1437Thrfs*114 with a substitution of leucine to threonine at 1437, additional 85 amino acids, and a stop at the frameshift 114th codon. Such a mutation is novel and has not previously been described. OI cases with mutations in exon 52 near the carboxyl-terminal propeptide region of COL1A1 have been described. Currently, 10 mutations in exon 52 of COL1A1 have been reported according to OI variant database [12]. These mutations include: (1) c.4257C>T, substitution, silent mutation; (2) c.4292C>T, substitution, missense mutation,
p.Thr1431Ile, OI type IV; (3) c.4310T>A, substitution, missense mutation, p.Leu1437Gln, OI type II; (4) c.4321G>C, substitution, missense mutation, p.Asp1441His, OI type I; (5) c.4321G>T, substitution, missense mutation, p.Asp1441Tyr, OI type II; (6) c.4329_4340delinsAGACCAGGTC, insertion/deletion, frameshift mutation, p.Pro1444Aspfs*106, OI type I; (7) c.4338dupC, duplication, frameshift mutation, p.Val1447Argfs*104, OI type IB; (8) c.4343G>A, substitution, missense mutation, p.Gly1448Asp, OI type I/IV; (9) c.4358_4362del, deletion, frameshift mutation, p.Glu1453Argfs*96, OI type I; and (10) c.4391T>C, substitution, missense mutation, p.Leu1464Pro, OI type III. Rugolotto et al [13] reported OI type II in a neonate with a missense mutation in exon 52 of COL1A1 (T>A, g.16310AF_017178) which converts the codon 1437 from leucine (CTG) to glutamine (CAG) along the pro1(I) carboxyl-terminal peptide. Fuccio et al [14] reported a missense mutation of c.4292C>T, p.T1432I (Thr_Ile) in exon 52 of COL1A1 in a patient with OI type IV. The present case was associated with OI type III which is severe and progressively deforming with grayish sclerae, DI, short stature and moderate deformity at birth [1,5,15]. The severity of autosomal dominant OI increases in the order of type I < type IV < type III < type II. OI type II is perinatally lethal, and type I is mild and non-deforming with no limb deformity.
The affected living girl in this presentation had upper limb paralysis at birth, mimicking shoulder dislocation or subluxation, birth trauma of the upper limbs, brachial plexus injury and clavicle fractures. OI may be undetected prenatally, and the postnatal manifestations may be mistaken as birth trauma. Rapid diagnosis of OI after birth is necessary for proper pediatric managements and parental counseling to avoid medical legal problems under such a circumstance. Recent studies have suggested that cesarean delivery might not protect against fractures in infants with OI, and whenever vaginal delivery is chosen, instrumentation should be minimized to avoid intracranial trauma of the affected fetuses [16].
The peculiar aspect of the present case is the recurrence of autosomal dominant OI in the offspring of unaffected parents with paternal gonadal mosaicism. Genetic counseling of recurrent autosomal dominant OI should include a thorough mutational analysis of the family members, and
mutational analysis of the sperms may detect paternal gonadal mosaicism for the mutation. It has been suggested that in familial autosomal dominant OI with one affected parent, the recurrent risk is 50%; in the presence of carriers of an autosomal recessive mutation in both parents, the recurrent risk is 25%; in case of parental mosaicism, the recurrent risk for autosomal dominant OI is variable but can be up to 50%; in case of unaffected parents with parental gonadal mosaicism, the empirical risk of recurrence ranges from 1% to 3%; and in the absence of parental somatic mosaicism, gonadal mosaicism, or recessive or dominant inheritance, the recurrent risk is probably below 1% [17-21].
In summary, we present prenatal diagnosis of recurrent autosomal dominant OI associated with a mutation in the COL1A1 gene arising from paternal gonadal mosaicism in the unaffected father. Our case adds to the examples of recurrent autosomal dominant OI caused by paternal gonadal mosaicism for a mutation in the COL1A1 gene.
Acknowledgements
This work was supported by research grants NSC-99-2628-B-195-001-MY3 and NSC-101-2314-B-195-011-MY3 from the National Science Council, and MMH-E-101-04 from Mackay Memorial Hospital, Taipei, Taiwan.
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Figure Legends
Fig. 1. Molecular analysis of the affected daughter shows an insertion frameshift mutation of c.4308_4309insA in exon 52 of the COL1A1 gene.
Fig. 2. Molecular analysis of the parental bloods, paternal sperms and amniocytes. The amniocytes have an insertion frameshift mutation of c.4308_4309insA in exon 52 of the COL1A1 gene. The sperms have mosaicism for the mutation. The parental bloods do not have such a mutation.
