A 30-year-old woman (gravida 2, para 1) felt reduced fetal movement compared with her previous pregnancy. The prenatal ultrasound scan showed obvious bilateral knee joint contractures, talipes equinovarus and inflexion and increased thickness of planta skin (6.8 mm) at 31 weeks (Fig. 1A). Karyotype and chromosomal microarray of amniocytes were normal. MLPA detected no deletion of exons 7 and 8 in SMN1. The women underwent vaginal delivery at 37 weeks. A female baby weighing 2,250 g was born cyanotic and with dyspnea. The baby had generalized hypotonia, lack of spontaneous limb movements, bilateral elbow, hip and knee flexion contractures and mild skin edema. The baby passed away at 16 days of age due to severe respiratory failure and pneumonia.
Trio-based WES identified compound heterozygous variants, c.543del (p. Ser182Profs*17) and c.1516A>C (p. Thr506Pro) in KLHL40 in the patient (Fig. 2a). Both asymptomatic parents were heterozygous carriers. The paternally inherited frameshift variant is novel, and it leads to a premature termination codon in the BACK domain that consequently results in loss-of-function of KLHL40. The maternally inherited missense variant has been proven to be a founder mutation in ethnic Chinese individuals . Both variants can be classified as pathogenic according to the ACMG/AMP guidelines .
A 28-year-old nulliparous woman presented with reduced fetal movement and progressive polyhydramnios. Amniocentesis showed a normal karyotype and chromosomal microarray. She underwent cesarean section at 35 weeks due to membrane rupture, and 2,600 ml of liquid was noted during delivery. A male baby weighing 2,150 g was born apneic and hypotonic. Multiple abnormalities were noted, including distinctive facial features (prominent forehead, hypertelorism, low-set ears and broad nasal bridge), severe hypotonia, multiple joint contractures, spontaneous limb fractures, bilateral clubfeet, talipes valgus, absent palmar and plantar crease, wide space between fingers and toes and cryptorchidism. The baby suffered from severe pneumonia and passed away at 20 days of age.
Trio-based WES identified compound heterozygous variants, c.602G>A (p. Trp201Ter) and c.1516A>C (p. Thr506Pro) in KLHL40 in the patient, which were inherited from the father and mother, respectively (Fig. 2b). The paternally inherited nonsense variant was predicted to truncate the BACK domain of KLHL40. Both variants can be categorized as pathogenic according to the ACMG/AMP guidelines .
A 27-year-old woman in her first pregnancy underwent an anomaly scan at 17 weeks of gestation, and the fetus was incidentally found to have bilateral talipes equinovarus. Persistent ultrasonic scans confirmed the condition at 21, 23 and 25 weeks of gestation. Then, the woman felt progressively reduced fetal movement. Amniocentesis showed a normal karyotype and chromosomal microarray. The ultrasonic scan at 29 weeks of gestation showed a fetus with abnormal posture, including persistently closed hands, flexed wrists, extended legs and knee joint contractures in addition to bilateral talipes equinovarus. In addition, there was increased thickness in the soft tissue of the forehead (7.9 mm), suggesting fetal edema (Fig. 1B). The pregnancy was terminated at 30 weeks of gestation.
Trio-based WES revealed a homozygous variant, c.1516A>C (p. Thr506Pro) in KLHL40, in a DNA sample from the aborted fetus. Both parents were asymptomatic heterozygous carriers (Fig. 2c).
Patients 4 And 5
A 27-year-old nulliparous woman in her first pregnancy felt persistently reduced fetal movement. The prenatal scan at 26 weeks incidentally detected polyhydramnios. Serial ultrasound showed fetal growth retardation and progressive polyhydramnios and no obvious limb movements. The women underwent vaginal delivery at 31 weeks due to preterm premature membrane rupture resulting from polyhydramnios. A female baby weighing 1,500 g was born cyanotic with no respiratory effort. The baby had generalized hypotonia, dysphagia and akinesia and required ventilation support and tube feeding. She once suffered from pleural effusion and sepsis and eventually recovered from active treatment. She was given special care, including daily physical massage and extremity fixation using bone fixation devices. At five years old, no obvious joint contractures or fractures were noted. However, she was still akinetic, with facial muscle involvement. Her eyes would open during both waking and sleeping states. She was able to slightly shake her head, move her mouth and eyes and feel emotion, but she was not able to vocalize or move her trunk, extremities and facial muscles. She can cry, maintains minimal eye contact and responds to ambient events or personal interactions. She showed aversion or reluctance when her blood was drawn or when her parents left her alone. Her nerve conduction velocity was normal, and electromyography implied myopathy. Karyotype and chromosomal microarray results were normal. MLPA detected no deletion of exons 7 and 8 in SMN1. However, WES was not performed for the family.
The woman had another unplanned spontaneous pregnancy. Again, she experienced reduced fetal movement and progressive polyhydramnios that were strikingly similar to her previous pregnancy. The anomaly scan at 28 weeks of gestation showed a fetus with abnormal posture, including closed hands, flexed wrists, bilateral knee contractures and clubfeet. Then, the woman decided to terminate the pregnancy and undergo whole-exome sequencing.
Trio-based WES revealed a homozygous variant, c.1516A>C (p. Thr506Pro) in KLHL40, in a DNA sample from the aborted fetus. Both parents were asymptomatic heterozygous carriers (Fig. 2d). Next, we analyzed the DNA sample of the girl patient, which had been still retained in our laboratory, and it expectedly revealed the same KLHL40 homozygous variant.